Stress and Addiction

Stress often causes porn addiction relapsesStress is a major factor in causing relapses in all addictions. Stress can take many forms, but it's our reaction that causes the neurochemical cascades that urge us to use.

This section contains both lay articles for the general public, and research articles. If you are not an expert in addiction, I suggest starting with the lay articles, they are marked with an "L".

(L) Studies Link Stress and Addiction

Minimize stress to overcome porn addictionBy Steven Stocker, NIDA NOTES Contributing Writer

Drug-addicted patients who are trying to remain off drugs can often resist the cravings brought on by seeing reminders of their former drug life, NIDA-funded researcher Dr. Mary Jeanne Kreek of Rockefeller University in New York City has noted. "For 6 months or so, they can walk past the street corner where they used to buy drugs and not succumb to their urges. But then all of a sudden they relapse," she says. "When we ask them why they relapse, almost always they tell us something like, 'Well, things weren't going well at my job,' or 'My wife left me.' Sometimes, the problem is as small as 'My public assistance check was delayed,' or 'The traffic was too heavy.'"

Anecdotes such as these are common in the drug abuse treatment community.

These anecdotes plus animal studies on this subject point toward an important role for stress in drug abuse relapse. In addition, the fact that addicts often relapse apparently in response to what most people would consider mild stressors suggests that addicts may be more sensitive than nonaddicts to stress.

This hypersensitivity may exist before drug abusers start taking drugs and may contribute to their initial drug use, or it could result from the effects of chronic drug abuse on the brain, or its existence could be due to a combination of both, Dr. Kreek has proposed. She has demonstrated that the nervous system of an addict is hypersensitive to chemically induced stress, which suggests that the nervous system also may be hypersensitive to emotional stress.

How the Body Copes With Stress

The body reacts to stress by secreting two types of chemical messengers - hormones in the blood and neurotransmitters in the brain. Scientists think that some of the neurotransmitters may be the same or similar chemicals as the hormones but acting in a different capacity.

Some of the hormones travel throughout the body, altering the metabolism of food so that the brain and muscles have sufficient stores of metabolic fuel for activities, such as fighting or fleeing, that help the person cope with the source of the stress. In the brain, the neurotransmitters trigger emotions, such as aggression or anxiety, that prompt the person to undertake those activities.

Normally, stress hormones are released in small amounts throughout the day, but when the body is under stress the level of these hormones increases dramatically. The release of stress hormones begins in the brain. First, a hormone called corticotropin-releasing factor (CRF) is released from the brain into the blood, which carries the CRF to the pituitary gland, located directly underneath the brain. There, CRF stimulates the release of another hormone, adrenocorticotropin (ACTH), which, in turn, triggers the release of other hormones - principally cortisol - from the adrenal glands. Cortisol travels throughout the body, helping it to cope with stress. If the stressor is mild, when the cortisol reaches the brain and pituitary gland it inhibits the further release of CRF and ACTH, which return to their normal levels. But if the stressor is intense, signals in the brain for more CRF release outweigh the inhibitory signal from cortisol, and the stress hormone cycle continues.

Researchers speculate that CRF and ACTH may be among the chemicals that serve dual purposes as hormones and neurotransmitters. The researchers posit that if, indeed, these chemicals also act as neurotransmitters, they may be involved in producing the emotional responses to stress.
The stress hormone cycle is controlled by a number of stimulatory chemicals in addition to CRF and ACTH and inhibitory chemicals in addition to cortisol both in the brain and in the blood.
Among the chemicals that inhibit the cycle are neurotransmitters called opioid peptides, which are chemically similar to opiate drugs such as heroin and morphine. Dr. Kreek has found evidence that opioid peptides also may inhibit the release of CRF and other stress-related neurotransmitters in the brain, thereby inhibiting stressful emotions.

How Addiction Changes the Body's Response to Stress

Heroin and morphine inhibit the stress hormone cycle and presumably the release of stress-related neurotransmitters just as the natural opioid peptides do. Thus, when people take heroin or morphine, the drugs add to the inhibition already being provided by the opioid peptides. This may be a major reason that some people start taking heroin or morphine in the first place, suggests Dr. Kreek. "Every one of us has things in life that really bother us," she says. "Most people are able to cope with these hassles, but some people find it very difficult to do so. In trying opiate drugs for the first time, some people who have difficulty coping with stressful emotions might find that these drugs blunt those emotions, an effect that they might find rewarding. This could be a major factor in their continued use of these drugs."

When the effects of opiate drugs wear off, the addict goes into withdrawal. Research has shown that, during withdrawal, the level of stress hormones rises in the blood and stress-related neurotransmitters are released in the brain. These chemicals trigger emotions that the addict perceives as highly unpleasant, which drive the addict to take more opiate drugs. Because the effects of heroin or morphine last only 4 to 6 hours, opiate addicts often experience withdrawal three or four times a day. This constant switching on and off of the stress systems of the body heightens whatever hypersensitivity these systems may have had before the person started taking drugs, Dr. Kreek says. "The result is that these stress chemicals are on a sort of hair-trigger release. They surge at the slightest provocation," she says.

Studies have suggested that cocaine similarly heightens the body's sensitivity to stress, although in a different way. When a cocaine addict takes cocaine, the stress systems are activated, much like when an opiate addict goes into withdrawal, but the person perceives this as part of the cocaine rush because cocaine is also stimulating the parts of the brain that are involved in feeling pleasure. When cocaine's effects wear off and the addict goes into withdrawal, the stress systems are again activated - again, much like when an opiate addict goes into withdrawal. This time, the cocaine addict perceives the activation as unpleasant because the cocaine is no longer stimulating the pleasure circuits in the brain. Because cocaine switches on the stress systems both when it is active and during withdrawal, these systems rapidly become hypersensitive, Dr. Kreek theorizes.

Evidence for the Link Between Stress and Addiction

This theory about stress and drug addiction is derived in part from studies conducted by Dr. Kreek's group in which addicts were given a test agent called metyrapone. This chemical blocks the production of cortisol in the adrenal glands, which lowers the level of cortisol in the blood. As a result, cortisol is no longer inhibiting the release of CRF from the brain and ACTH from the pituitary. The brain and pituitary then start producing more of these chemicals.

Physicians use metyrapone to test whether a person's stress system is operating normally. When metyrapone is given to nonaddicted people, the ACTH level in the blood increases. However, when Dr. Kreek and her colleagues administered metyrapone to active heroin addicts, the ACTH level hardly rose at all. When the scientists gave metyrapone to heroin addicts who were abstaining from heroin use and who were not taking methadone, the synthetic opioid medication that suppresses cravings for opiate drugs, the ACTH level in the majority of the addicts increased about twice as high as in nonaddicts. Finally, when the scientists gave metyrapone to heroin addicts maintained for at least 3 months on methadone, the ACTH level rose the same as in nonaddicts.

Addicts on heroin underreact because all the excess opioid molecules in the brain greatly inhibit the brain's stress system, Dr. Kreek explains. Addicts who are heroin-free and methadone-free overreact because the constant on-off of daily heroin use has made the stress system hypersensitive, she says, and heroin addicts who are on methadone react normally because methadone stabilizes this stress system. Methadone acts at the same sites in the brain as heroin, but methadone stays active for about 24 hours while the effects of heroin are felt for only 4 to 6 hours. Because methadone is long-acting, the heroin addict is no longer going into withdrawal three or four times a day. Without the constant activation involved in these withdrawals, the brain's stress system normalizes.

Recently, Dr. Kreek's group reported that a majority of cocaine addicts who are abstaining from cocaine use overreact in the metyrapone test, just like the heroin addicts who are abstaining from heroin and not taking methadone. As with heroin addicts, this overreaction in cocaine addicts reflects hypersensitivity of the stress system caused by chronic cocaine abuse.

"We think that addicts may react to emotional stress in the same way that their stress hormone system reacts to the metyrapone test," says Dr. Kreek. At the slightest provocation, CRF and other stress-related neurotransmitters pour out into the brain, producing unpleasant emotions that make the addict want to take drugs again, she suggests. Since life is filled with little provocations, addicts in withdrawal are constantly having their stress system activated, she concludes.

(L) The Rat Park, Addiction, and Environmental Factors - an essay (2007)

Loss of the things that kept our ancestors' brains in balance leaves us more vulnerable to pornography addictionImportant essay on the "Rat Park" experiments, in which researchers found out how important environment is to addiction. Our environment has drastically changed from from our hunter-gatherer days, which I believe makes us more vulnerable to porn addiction.

Rat Trap
Why Canada’s drug policy won’t check addiction

by Robert Hercz

From the December 2007 issue of The Walrus
   
“Canada’s anti-drug strategy a failure, study suggests,” read the headline of a brief cbc story that circulated through a handful of news outlets before dying out early this year. The British Columbia Centre for Excellence in hiv/aids had just published a paper revealing that almost three-quarters of the $368 million allocated to Canada’s Drug Strategy in 2004–2005 was spent on enforcement initiatives aimed at staunching the supply of drugs. The authors pointed out that despite this war on drugs, the rate of consumption was higher than ever: in 2002, 45 percent of Canadians reported having used illicit drugs in their lives, up from 28.5 percent in 1994.

The study advocated that money be directed toward cost-effective, evidence-based prevention, treatment, and harm-reduction programs — the other three pillars of Canada’s drug policy. But to Bruce Alexander, a psychologist who recently retired after thirty-five years at Simon Fraser University in British Columbia, the policy debate is just a distraction. “There’s no drug policy that will have much effect on addiction,” he says from his home in Vancouver. “I think that’s one of our diversions: ‘If we could just get the drug policy right, we’d solve our addiction problem.’ I don’t think that would touch it. The only way we’ll ever touch the problem of addiction is by developing and fostering viable culture.”

Alexander has been delivering this message since the late 1970s, when he ran a series of elegant experiments he calls Rat Park, which led him to conclude that drugs — even such hard drugs as heroin and cocaine — do not cause addiction; the user’s environment does. It was a stunning result, one that should have had a seismic effect on drug policy. But, like the report on Canada’s failed drug strategy, Alexander’s research was largely ignored.

When Richard Nixon launched the War on Drugs in the early 1970s, it was generally believed, as it is today, that drugs cause addiction as surely as lightning causes thunder. At that time, Bruce Alexander was counselling addicts in Vancouver’s infamous Downtown Eastside, and he wasn’t so sure. “Junkies say things like ‘I can go through the withdrawal, and I can stop, but I don’t want to stop,’” Alexander says. “We’re not supposed to believe it; we’re supposed to say they’re denying that they’re in the grip of this drug, but they’re not, really. I believed them.”

His suspicions carried little weight in the classroom, however, where students were armed with a powerful trump card: the famous Skinner box experiments of the 1950s and ’60s. A Skinner box is a cage equipped to condition an animal’s behaviour through reward or punishment. In a typical drug test, a surgically implanted catheter is hooked up to a drug supply that the animal self-administers by pressing a lever. Hundreds of trials showed that lab animals readily became slaves to such drugs as heroin, cocaine, and amphetamines. “They were said to prove that these kinds of dope are irresistible, and that’s it, that’s the end of the addiction story right there,” Alexander says. After one particularly fruitless seminar in 1976, he decided to run his own tests.

The problem with the Skinner box experiments, Alexander and his co-researchers suspected, was the box itself. To test that hypothesis, Alexander built an Eden for rats. Rat Park was a plywood enclosure the size of 200 standard cages. There were cedar shavings, boxes, tin cans for hiding and nesting, poles for climbing, and plenty of food. Most important, because rats live in colonies, Rat Park housed sixteen to twenty animals of both sexes.

Rats in Rat Park and control animals in standard laboratory cages had access to two water bottles, one filled with plain water and the other with morphine-laced water. The denizens of Rat Park overwhelmingly preferred plain water to morphine (the test produced statistical confidence levels of over 99.9 percent). Even when Alexander tried to seduce his rats by sweetening the morphine, the ones in Rat Park drank far less than the ones in cages. Only when he added naloxone, which eliminates morphine’s narcotic effects, did the rats in Rat Park start drinking from the water-sugar-morphine bottle. They wanted the sweet water, but not if it made them high.

In a variation he calls “Kicking the Habit,” Alexander gave rats in both environments nothing but morphine-laced water for fifty-seven days, until they were physically dependent on the drug. But as soon as they had a choice between plain water and morphine, the animals in Rat Park switched to plain water more often than the caged rats did, voluntarily putting themselves through the discomfort of withdrawal to do so.

Rat Park showed that a rat’s environment, not the availability of drugs, leads to dependence. In a normal setting, a narcotic is an impediment to what rats typically do: fight, play, forage, mate. But a caged rat can’t do those things. It’s no surprise that a distressed animal with access to narcotics would use them to seek relief.

Rat Park overtrumped the Skinner box trump card. “You could no longer say with a straight face that rats find certain drugs irresistible,” Alexander says. He was disappointed, then, when, his work was rejected by both Science and Nature, two of the world’s most prestigious scientific journals (even though both reject over 90 percent of submissions). Peer reviewers didn’t fault the methodology; their objection, recalled study co-author Barry Beyerstein, amounted to “I can’t put my finger on what’s wrong, but I know it’s got to be wrong.” Ultimately, the Rat Park papers were published in reputable psychopharmacology journals, “but not ones that reached the public,” Alexander says.

(L) Stress Hormone CRF Key to Development of Alcohol Dependence (2010)

A team of scientists from The Scripps Research Institute has found that a specific stress hormone, the corticotropin-releasing factor (CRF), is key to the development and maintenance of alcohol dependence in animal models. Stress and addiction, including porn addiction, go together.

“I’m excited about this study,” said Associate Professor Marisa Roberto, who led the research. “It represents an important step in understanding how the brain changes when it moves from a normal to an alcohol-dependent state.”

The new study not only confirms the central role of CRF in alcohol addiction using a variety of different methods, but also shows that in rats the hormone can be blocked on a long-term basis to alleviate the symptoms of alcohol dependence.

Previous research had implicated CRF in alcohol dependence, but had shown the effectiveness of blocking CRF only in acute single doses of an antagonist (a substance that interferes the physiological action of another). The current study used three different types of CRF antagonists, all of which showed an anti-alcohol effect via the CRF system. In addition, the chronic administration of the antagonist for 23 days blocked the increased drinking associated with alcohol dependence.

Alcoholism, a chronic disease characterized by compulsive use of alcohol and loss of control over alcohol intake, is devastating both to individuals and their families and to society in general. About a third of the approximately 40,000 traffic fatalities every year involve drunk drivers, and direct and indirect public health costs are estimated to be in the hundreds of billions of dollars yearly.

“Research to understand alcoholism is important for society,” said Roberto, a 2010 recipient of the prestigious Presidential Early Career Award for Scientists and Engineers. “Our study explored what we call in the field ‘the dark side’ of alcohol addiction. That’s the compulsion to drink, not because it is pleasurable-which has been the focus of much previous research-but because it relieves the anxiety generated by abstinence and the stressful effects of withdrawal.”

CRF is a natural substance involved in the body’s stress response. Originally found only in the area of the brain known as the hypothalamus, it has now been localized in other brain regions, including the pituitary, where it stimulates the secretion of corticotropin and other biologically active substances, and the amygdala, an area that has been implicated in the elevated anxiety, withdrawal, and excessive drinking associated with alcohol dependence.

To confirm the role of CRF in the central amygdala for alcohol dependence, the research team used a multidisciplinary approach that included electrophysiological methods not previously applied to this problem.

The results from these cellular studies showed that CRF increased the strength of inhibitory synapses (junctions between two nerve cells) in neurons in a manner similar to alcohol. This change occurred through the increased release of the neurotransmitter GABA, which plays an important role in regulating neuronal excitability.

Next, the team explored if the effects of CRF could be blocked through the administration of CRF antagonists. To do this, the scientists tested three different CRF1 antagonists (called antalarmin, NIH-3, and R121919) against alcohol in brain slices and injected R121919 for 23-days into the brains of rats that were exposed to conditions that would normally produce a dependence on alcohol.

Remarkably, the behavior of the “alcohol-dependent” rats receiving one of the CRF antagonists (R121919) mimicked their non-addicted (“naive”) counterparts. Instead of seeking out large amounts of alcohol like untreated alcohol-dependent rats, both the treated rats and their non-addicted brethren self-administered alcohol in only moderate amounts.

“This critical observation suggests that increased activation of CRF systems mediates the excessive drinking associated with development of dependence,” said Roberto. “In other words, blocking CRF with prolonged CRF1 antagonist administration may prevent excessive alcohol consumption under a variety of behavioral and physiological conditions.”

Importantly, in the study the rats did not exhibit tolerance to the suppressive effects of R121919 on alcohol drinking. In fact, they may have become even more sensitive to its effects over time-a good sign for the efficacy of this type of compound as it might be used repeatedly in a clinical setting.

The scientists’ cellular studies also supported the promising effects of CRF1 antagonists. All of the CRF antagonists decreased basal GABAergic responses and abolished alcohol effects. Alcohol-dependent rats exhibited heightened sensitivity to CRF and the CRF1 antagonists on GABA release in the central amygdala region of the brain. CRF1 antagonist administration into the central amygdala reversed dependence-related elevations in extracellular GABA and blocked alcohol-induced increases in extracellular GABA in both dependent and naive rats. The levels of CRF and CRF1 mRNA in the central amygdala of dependent rats were also elevated.

Roberto notes that another intriguing aspect of the work is that it provides a possible physiological link between stress-related behaviors, emotional disorders (i.e. stress disorders, anxiety, depression), and the development of alcohol dependence.

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References:
1. Marisa Roberto, et al. Corticotropin Releasing Factor-Induced Amygdala Gamma-Aminobutyric Acid Release Plays a Key Role in Alcohol Dependence. Biological Psychiatry, doi:10.1016/j.biopsych.2009.11.007

(L) Reward-Stress Link Points to New Addiction Targets (2009)

BY: LEIGH MACMILLANStress and reward may both play a role in porn addiction

1/09/2009 - Rewarding and stressful signals don't seem to have much in common. But researchers studying diseases ranging from drug addiction to anxiety disorders are finding that the brain's reward and stress signaling circuits are intertwined in complex ways.

Vanderbilt Medical Center investigators have now discovered a functional link between reward and stress. They found that dopamine — the brain's chief reward signal — works through corticotrophin-releasing factor (CRF) — the brain's main stress signal — to increase the activity of a brain region involved in addiction relapse.

The findings, reported in The Journal of Neuroscience, point to new potential targets for treating alcohol and drug abuse — particularly the problem of relapse.

It is widely accepted that stress is a key signal in prompting alcohol and drug abuse relapse.

“Even after long periods of abstinence, an individual is at risk for relapse, and stress is what's most frequently cited as initiating that relapse,” said Danny Winder, Ph.D., associate professor of Molecular Physiology & Biophysics and an investigator in the Center for Molecular Neuroscience and the Vanderbilt Kennedy Center.

Studies in animal models had suggested that a brain region called the extended amygdala — an area that extends anatomically between reward and stress centers — and CRF within this region were involved in stress-induced reinstatement (relapse) behavior.

It was also known that alcohol and drugs of abuse increase dopamine levels, not just in the “classical” reward circuitry in the brain, but also in the extended amygdala. It was not clear, however, what dopamine did in this region.

Thomas Kash, Ph.D., a research instructor in Winder's laboratory, decided to explore dopamine's actions in the extended amygdala. Using an in vitro brain slice system, he discovered that dopamine increased excitatory glutamate signaling in this brain region. Surprisingly, he found that dopamine required CRF signaling to increase glutamate signaling.

The researchers next looked for this mechanism in animals. William Nobis, an M.D./Ph.D. student, injected mice with cocaine and studied signaling in brain slices. His studies confirmed that in vivo administration of cocaine engaged the dopamine-CRF signaling cascade that the team had discovered in vitro.

“We think that when an individual takes a drug of abuse or alcohol, it causes a rise in dopamine levels in the extended amygdala, and that likely engages this CRF signaling cascade in this region,” Winder said. “That's now activating portions of this brain structure, which then communicate with the core addiction reward circuitry. We believe the dopamine-CRF signaling may be a key initial step in promoting reinstatement behavior.”

The findings suggest a new target to consider for therapeutics that might address stress-induced reinstatement, Winder said.

“If we can hone in on the mechanisms of this dopamine-CRF interaction, if we can identify the key population of CRF cells, then we could start to think of approaches to silence those cells.”
Such a therapy would be extremely valuable, Winder noted.
“Essentially all of the pharmacotherapies for addiction to date help people get through the withdrawal phase,” he said. “There's really nothing available to reduce the likelihood of relapse.”

The studies add to a growing number of research findings that point to the interwoven nature of the brain's reward and stress circuitry. Investigators need to be looking beyond dopamine and the classical reward circuitry — long considered the “common target” of drugs of abuse — to understand mechanisms underlying addiction-related behaviors, Winder said.

“The recruitment of CRF signaling may be another common feature of drugs of abuse.”

Robert Matthews, Ph.D., research associate professor in the Department of Molecular Physiology & Biophysics, also contributed to the studies. The National Institutes of Health supported the research.
Kash was recently awarded a Pathway to Independence Award by the National Institute on Alcohol Abuse and Alcoholism in support of his continuing efforts to characterize dopamine action in the extended amygdala. He will be focusing on dopamine's role in mediating the acute actions of alcohol.

(L) Mice raised under stressful conditions are more adaptable as adults—and may pass this trait on to their pups (2014)

Upside of Early-Life Stress?

Mice raised under stressful conditions are more adaptable as adults—and may pass this trait on to their pups.

By Kate Yandell | November 18, 2014

A number of studies indicate that stress experienced in very young animals or humans can have negative effects on mental and cognitive health that can later be passed on to offspring through epigenetic modification. But early-life stress in mice can also have positive effects that can be passed on to pups, according to a study published today (November 18) in Nature Communications. The pups of stressed male mice were behaviorally flexible, as shown by their ability to complete tasks that required waiting or adjusting their behavior over time. And these pups had altered modifications in their hippocampi to histones associated with the mineralocorticoid receptor gene, which is involved in stress response.

“People have shown many times that the negative effects of stress can be passed to the next generation,” said Deena Walker, a neuroscience postdoc at Mount Sinai School of Medicine in New York City who was not involved in the research. “It’s interesting . . . that now we’re seeing some of those beneficial effects of stress being passed, as well.”

“The effect of trauma may be overall negative, but [it] may also provide some positive sides,” said study coauthor Isabelle Mansuy, a professor of neuroepigenetics at the University of Zürich and the Swiss Federal Institute of Technology.

Mansuy and her colleagues subjected newborn mice to unpredictable maternal separation combined with unpredictable maternal stress (MSUS) for two weeks. MSUS entails taking away the pups’ mothers at unpredictable intervals and subjecting their mothers to stressful situations, such as being placed in cramped tubes or in cups of cold water. The team was “trying to replicate hectic conditions during early life involving neglect, unpredictability, and unreliable care,” said Mansuy.

The researchers then made the mice complete tasks that required them to follow rapidly changing rules to get water and food. For instance, in one task, the mice got a reward if they poked their noses into a hole at the right time after a delay, signaled by light. When the delay was short, control and MSUS mice performed similarly, but with a longer delay, mice that had been stressed early in life outperformed controls. When the researchers bred MSUS males with wild-type females, the resulting offspring similarly excelled at the nose poke test.

The researchers also performed some tests with only female pups and no fathers, since these tasks required housing mice in group cages that can disturb male hierarchies. In one test, the mice first got a drink if they alternated between visiting two corners of a cage opposite one another. Later, the animals only got the reward if they moved diagonally between the other two corners of the cage. The daughters of MSUS mice successfully completed the tasks more often than control animals did.

“I think [MSUS] provides an advantage in challenging conditions,” said Mansuy. “Because [the mice] have been put in such traumatic conditions . . . they develop strategies to be better when their life is somehow threatened.”

The researchers next set out to determine how the mice were acquiring and passing on these behavioral traits. They decided to examine expression of the mineralocorticoid receptor, which plays roles in stress response, anxiety, and goal-directed behavior. They found that it was underexpressed in the hippocampi of MSUS mice and their pups. While DNA methylation levels between control and stressed mice at the mineralocorticoid receptor were similar, acetylation and and some types of methylation of nearby histones were reduced in the offspring of the MSUS mice.

When the researchers injected mice with enzymes that block acetylation and methylation, the mineralocorticoid receptor’s expression was repressed. Likewise, when they injected mice with these enzymes or blocked the mineralocorticoid receptor, the mice showed similar behavioral changes to those observed in the MSUS mice. The team “did a really nice job using pharmacological inhibitors to sort of replicate the finding that they’d seen with the stressor,” said Walker.

It remains unclear exactly how the stressed male mice pass on their behaviors to pups. The researchers found that the sperm of the stressed fathers had elevated DNA methylation on a promoter for the mineralocorticoid receptor.

But Sarah Kimmins, a reproductive biologist who studies epigenetics at McGill University in Montreal, did not find the DNA methylation findings to be meaningful. “Your methylation is within your error of your assay,” she said. Moreover, she said that the methylation levels were so low that they were unlikely to have a significant biological effect.

Mansuy says that a number of other epigenetic changes could also contribute to transmitting the trait. For instance, previous work out of her lab has indicated that changes in noncoding RNA abundance in sperm can transmit the effects of trauma across generations.

How epigenetic modifications in sperm escape the mass epigenetic reprogramming that comes after fertilization of an egg is still unknown. The general phenomenon of parental stress having effects on subsequent generation is real, said Kimmins. “The question is: How is it happening?”

Mansuy said that her lab continues to work on understanding how the effects of MSUS are transmitted to future generations. For now, the present study suggests that researchers should pay attention to neglect’s slight silver lining. “It was surprising to see that the behavioral flexibility was observed on different tasks, that it was observed in both males and females, and that it was transmitted across generations,” said Mansuy.

K. Gapp et al., “Early life stress in fathers improves behavioural flexibility in their offspring,” Nature Communications, doi:10.1038/ncomms6466, 2014.

A Role for Brain Stress Systems in Addiction (2008)

Neuron. Author manuscript; available in PMC Sep 22, 2009.

Published in final edited form as:

PMCID: PMC2748830

NIHMSID: NIHMS140623

See other articles in PMC that cite the published article.

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Abstract

Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take drugs and has been linked to dysregulation of brain regions that mediate reward and stress. Activation of brain stress systems is hypothesized to be key to the negative emotional state produced by dependence that drives drug seeking through negative reinforcement mechanisms. This review explores the role of brain stress systems (corticotropin-releasing factor, norepinephrine, orexin [hypocretin], vasopressin, dynorphin) and brain antistress systems (neuropeptide Y, nociceptin [orphanin FQ]) in drug dependence, with emphasis on the neuropharmacological function of extrahypothalamic systems in the extended amygdala. The brain stress and antistress systems may play a key role in the transition to and maintenance of drug dependence once initiated. Understanding the role of brain stress and antistress systems in addiction provides novel targets for treatment and prevention of addiction and insights into the organization and function of basic brain emotional circuitry.

1. Drugs, Addiction, and Stress: Introduction and Definitions

1.2. Dynamics of Addiction

Drug addiction is a chronically relapsing disorder characterized by compulsive drug use and loss of control over drug intake. Addiction comprises three stages: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect, in which impulsivity often dominates at the early stages, and compulsivity dominates at terminal stages. As an individual moves from impulsivity to compulsivity, a shift occurs from positive reinforcement driving the motivated behavior to negative reinforcement driving the motivated behavior (Koob, 2004). These three stages are conceptualized as feeding into one other, becoming more intense, and ultimately leading to the pathological state known as addiction (Koob and Le Moal, 1997). The preoccupation/anticipation (craving) stage of the addiction cycle has long been hypothesized to be a key element of relapse in humans and defines addiction as a chronic relapsing disorder (Tables 1 and ​and22).

Table 1 
Definitions
Table 2 
Stages of the Addiction Cycle

Different drugs produce different patterns of addiction that engage different components of the addiction cycle, depending on dose, length of use, and even cultural factors. With opioids, the classic drugs of addiction, a pattern of compulsive intravenous or smoked drug taking evolves that includes intense intoxication, the development of tolerance, escalation in intake, and profound dysphoria, physical discomfort, and somatic and emotional withdrawal signs during abstinence. A pattern develops in which the drug must be obtained to avoid the severe dysphoria and discomfort experienced during abstinence. Alcohol addiction or alcoholism can follow a similar trajectory, but the pattern of oral drug taking often is characterized by binges of alcohol intake that can be daily episodes or prolonged days of heavy drinking and is characterized by a severe somatic and emotional withdrawal syndrome. Nicotine addiction contrasts with the above patterns, with little obvious signs of the binge/intoxication stage, and has a pattern of intake characterized by highly titrated intake of the drug except during periods of sleep and negative emotional states during abstinence, including dysphoria, irritability, and intense craving. Marijuana addiction follows a pattern similar to opioids and tobacco, with a significant intoxication stage, but as chronic use continues, subjects begin to show a pattern of use characterized by chronic intoxication during waking hours followed by a withdrawal that includes dysphoria, irritability, and sleep disturbances. Psychostimulant addiction (cocaine and amphetamines) shows a pattern with a salient binge/intoxication stage. Such binges can be hours or days in duration and often are followed by a withdrawal (“crash”) characterized by extreme dysphoria and inactivity. Intense craving for all drugs can anticipate withdrawal (i.e., with opioids, alcohol, nicotine) or often occurs after acute withdrawal when craving is driven by both environmental cues signifying the availability of the drug and internal states linked to negative emotional states and stress.

Animal models of the symptoms of addiction on specific drugs such as stimulants, opioids, alcohol, nicotine, and Δ9-tetrahydrocannabinol can be defined by models relevant to different stages of the addiction cycle (Shippenberg and Koob, 2002) (Table 2). Animal models for the binge/intoxication stage of the addiction cycle can be conceptualized as measuring acute drug reward, in which reward can be defined as a positive reinforcer with some additional emotional value, such as pleasure (Table 1). Animal models of reward and reinforcement are extensive and well validated and include intravenous drug self-administration, conditioned place preference, and decreased brain reward thresholds. Animal models of the withdrawal/negative affect stage include conditioned place aversion (rather than preference) to precipitated withdrawal or spontaneous withdrawal from chronic administration of a drug, increases in brain reward thresholds, and dependence-induced increases in drug seeking (Table 2). Rodents will increase intravenous or oral self-administration of drugs with extended access to the drugs and during withdrawal from the dependent state, measured both by increased drug administration and increased work to obtain the drug. Such increased self-administration in dependent animals has been observed with cocaine, methamphetamine, nicotine, heroin, and alcohol (Ahmed et al., 2000; Ahmed and Koob, 1998; Kitamura et al., 2006; O’Dell and Koob, 2007; Roberts et al., 2000). This model will be a key element for the evaluation of the role of brain stress systems in addiction outlined below.

Animal models of craving (preoccupation/anticipation stage) involve reinstatement of drug seeking following extinction from the drugs themselves, by cues linked to the drug, and from exposure to stressors (Shaham et al., 2003) (Table 1). Drug-induced reinstatement first involves extinction and then a priming injection of the drug. Latency to reinitiate responding or the amount of responding on the previously extinguished lever are hypothesized to reflect the motivation for drug-seeking behavior. Similarly, drug-paired or drug-associated stimuli can reinitiate drug-seeking behavior (cue-induced reinstatement). Stress-induced reinstatement involves the application of acute stressors that reinitiate drug-seeking behavior in animals that have been extinguished from the drug. These stressors can include physical stressors such as footshock, psychological stressors such as restraint, or pharmacological stressors such as yohimbine (Shaham et al., 2003). In rats with a history of dependence, protracted abstinence can be defined as a period after acute physical withdrawal has disappeared in which elevations in ethanol intake over baseline and increased stress responsivity persist (e.g., 2–8 weeks postwithdrawal from chronic ethanol). Protracted abstinence has been linked to increased brain reward thresholds and increases in sensitivity to anxiety-like behavior that have been shown to persist after acute withdrawal in animals with a history of dependence. Stress-induced reinstatement of drug seeking and stress-induced reinstatement of anxiety-like states during protracted abstinence will be used in the present review to explore the role of the brain stress systems in the preoccupation-anticipation (craving) stage of the addiction cycle (Table 2).

The thesis of this review is that a key element of the addiction process involves a profound interaction with brain stress systems and dysregulation of brain antistress systems to produce the negative emotional state that becomes the powerful motivation for drug seeking associated with compulsive use in the withdrawal/negative affect and preoccupation/anticipation (craving) stages of the addiction cycle. Chronic use of drugs of abuse has long been associated with exaggerated responses to stressors, and these exaggerated responses contribute to addiction (Himmelsbach, 1941). Delineation of key elements of not only hormonal but also brain stress neurocircuits have laid the foundation for new insights into the pathophysiology of addiction.

1.3. Motivation, Opponent Process, and Stress

Motivation is a state that guides behavior in relationship to changes in the environment (Hebb, 1949) and shares key common characteristics with our concepts of arousal (Pfaff, 2006). Motivational states gain energy both from the external milieu (incentives) or internal milieu (central motive states or drives). As such, motivation or motivational states are not constant and vary over time but have long been hypothesized to have homeostatic constraints. In the context of temporal dynamics, Solomon and Corbit inextricably linked the concept of motivation with hedonic, affective, or emotional states in addiction by the opponent process theory of motivation (Solomon and Corbit, 1974) (Table 1).

More recently, opponent process theory has been expanded into the domains of the neurocircuitry and neurobiology of drug addiction from a physiological perspective (Koob and Le Moal, 2008). Counteradaptive processes such as opponent process that are part of the normal homeostatic limitation of reward function are hypothesized to fail to return to the normal homeostatic range and thus produce the reward deficits that are prominent in addiction. These counteradaptive processes were hypothesized to be mediated by two processes: within-system neuroadaptations and between-system neuroadaptations (Koob and Bloom, 1988) (Table 1).

For the present review, the systems activated as between-system neuroadaptations are hypothesized to involve the brain stress systems and the brain antistress systems. These circuits also can be conceptualized as an antireward homeostatic mechanism (Koob and Le Moal, 2008). In this framework, addiction is conceptualized as a cycle of spiraling dysregulation of brain reward/antireward mechanisms that progressively increases, resulting in the compulsive use of the drug. The purpose of this review is to explore the neuroadaptational changes that occur in the brain stress and antistress systems to account for the negative emotional state that provides motivation for the compulsivity of addiction.

1.4 Hypothalamic-Pituitary-Adrenal Axis

The hypothalamic-pituitary-adrenal (HPA) axis is defined by three major structures: the paraventricular nucleus of the hypothalamus, the anterior lobe of the pituitary gland, and the adrenal gland (for review, see Turnbull and Rivier, 1997). Neurosecretory neurons in the medial parvocellular subdivision of the paraventricular nucleus synthesize and release CRF into the portal blood vessels that enter the anterior pituitary gland. Binding of CRF to the CRF1 receptor on pituitary corticotropes induces the release of adrenocorticotropic hormone (ACTH) into the systemic circulation. ACTH, in turn, stimulates glucocorticoid synthesis and secretion from the adrenal cortex. Vasopressin released from parvocellular neurons of the paraventricular nucleus produces synergistic effects on ACTH release that are mediated by vasopressin V1b receptors. The HPA axis is finely tuned via negative feedback from circulating glucorticoids that act on the glucocorticoid receptor, a cytosolic protein that acts via the nucleus and transcriptional mechanisms, in two main brain areas: the paraventricular nucleus and the hippocampus. The hypophysiotropic neurons of the paraventricular nucleus of the hypothalamus are innervated by numerous afferent projections, including from brainstem, other hypothalamic nuclei, and forebrain limbic structures.

1.5. Extended Amygdala: Interface of Stress and Addiction

New functional observations have provided support for the hypothesis that the neuroanatomical substrates for many of the motivational effects of opponent processes associated with drug dependence may involve a common neural circuitry that forms a separate entity within the basal forebrain, termed the “extended amygdala” (Koob and Le Moal, 2001). The extended amygdala represents a macrostructure that is composed of several basal forebrain structures: the bed nucleus of the stria terminalis, the central medial amygdala, and a transition zone in the posterior part of the medial nucleus accumbens (i.e., posterior shell) (Heimer and Alheid, 1991). These structures have similarities in morphology, immunohistochemistry, and connectivity, and they receive afferent connections from limbic cortices, hippocampus, basolateral amygdala, midbrain, and lateral hypothalamus. The efferent connections from this complex include the posterior medial (sublenticular) ventral pallidum, ventral tegmental area, various brainstem projections, and perhaps most intriguing from a functional point of view, a considerable projection to the lateral hypothalamus (Heimer and Alheid, 1991). Key elements of the extended amygdala include not only neurotransmitters associated with the positive reinforcing effects of drugs of abuse but also major components of the brain stress systems associated with the negative reinforcement of dependence (Koob and Le Moal, 2005). The role of specific neuropharmacological mechanisms associated with the brain stress systems and the extended amygdala will be explored in the sections below.

2. Brain Stress Systems and Addiction: Corticotropin-Releasing Factor, Norepinephrine, Orexin, Vasopressin, Dynorphin

2.1. Corticotropin-Releasing Factor

Corticotropin-releasing factor is a 41 amino acid polypeptide that controls hormonal, sympathetic, and behavioral responses to stressors. Substantial CRF-like immunoreactivity is present in the neocortex, extended amygdala, medial septum, hypothalamus, thalamus, cerebellum, and autonomic midbrain and hind-brain nuclei (Swanson et al., 1983) (Figure 1). The CRF1 receptor has abundant, widespread expression in the brain that overlaps significantly with the distribution of CRF and urocortin 1. The discovery of other peptides with structural homology, notably the urocortin family (urocortins 1, -2, and -3), has suggested broad neurotransmitter roles for the CRF systems in behavioral and autonomic responses to stress (Bale and Vale, 2004) (see Supplemental Data available online). Urocortin 1 binds both to CRF1 and CRF2 receptors and has a different neuroanatomical distribution than CRF. The type 2 urocortins, urocortin 2 (Reyes et al., 2001) and urocortin 3 (Lewis et al., 2001), differ from urocortin 1 and CRF in their neuroanatomical, neuropharmacological, and distribution profiles and are endogenous selective CRF2 agonists.

Figure 1 
Localizations and Projections of Brain Stress Systems—Corticotropin-Releasing Factor

CRF in the paraventricular nucleus of the hypothalamus controls the pituitary adrenal response to stress (Turnbull and Rivier, 1997). Progressive changes in the HPA axis are observed during the transition from acute administration to chronic administration of drugs of abuse. Acute administration of most drugs of abuse in animals activates the HPA axis and may first facilitate activity in the brain motivational circuits, facilitate drug reward, and as a result facilitate acquisition of drug-seeking behavior (Piazza et al., 1993; Goeders, 1997; Piazza and Le Moal, 1997; Fahlke et al., 1996). With repeated administration of cocaine, opiates, nicotine, and alcohol, these acute changes are blunted or dysregulated (Kreek and Koob, 1998; Rasmussen et al., 2000; Goeders, 2002; Koob and Kreek, 2007; Sharp and Matta, 1993; Semba et al., 2004). An early hypothesis was that atypical responsivity to stressors contributes to the persistence and relapse to cycles of opioid dependence, and subsequently this hypothesis was extended to other drugs of abuse (Kreek and Koob, 1998).

Importantly for the current thesis, high circulating levels of glucocorticoids can feed back to shut off the HPA axis but can “sensitize” CRF systems in the central nucleus of the amygdala and norepinephrine systems in the basolateral amygdala that are known to be involved in behavioral responses to stressors (Imaki et al., 1991; Makino et al., 1994; Swanson and Simmons, 1989; Schulkin et al., 1994; Shepard et al., 2000). Thus, while activation of the HPA axis may characterize initial drug use and the binge/intoxication stage of addiction, the HPA activation also can lead to subsequent activation of extrahypothalamic brain stress systems that characterize the withdrawal/negative affect stage of addiction (Kreek and Koob, 1998; Koob and Le Moal, 2005; Koob and Kreek, 2007) (Figure 2).

Figure 2 
Effects of Drug Withdrawal on CRF Levels in the Amygdala

Substantial evidence now suggests that brain extrahypothalamic CRF systems are activated during the development of dependence on alcohol, and this activation has motivational significance. During ethanol withdrawal, CRF release increases within the central nucleus of the amygdala and bed nucleus of the stria terminalis of dependent rats (Funk et al., 2006; Merlo-Pich et al., 1995; Olive et al., 2002) (Figures 1B and ​and2),2), and this dysregulation of brain CRF systems is hypothesized to underlie both the enhanced anxiety-like behaviors and enhanced ethanol self-administration associated with ethanol withdrawal. Supporting this hypothesis, systemic CRF1 antagonists (Overstreet et al., 2004) or the subtype nonselective CRF receptor antagonists α-helical CRF9-41 and D-Phe CRF12-41 when injected intracerebroventricularly (Baldwin et al., 1991) or directly into the central nucleus of the amygdala (Rassnick et al., 1993) reduced ethanol withdrawal-induced anxiety-like behavior.

Exposure to repeated cycles of chronic ethanol vapor to induce dependence substantially increased ethanol intake in rats, both during acute withdrawal and during protracted abstinence (2 weeks postacute withdrawal) (O’Dell et al., 2004; Rimondini et al., 2002). Intracerebroventricular administration and direct intracerebral administration into the central nucleus of the amygdala of a CRF1/CRF2 peptide antagonist selectively blocked the dependence-induced increase in ethanol self-administration during acute withdrawal (Valdez et al., 2004). Systemic injections of small-molecule CRF1 antagonists also blocked the increased ethanol intake associated with acute ethanol withdrawal (Knapp et al., 2004; Funk et al., 2007; Richardson et al., 2008) (Figure 3). A CRF2 agonist injected into the central nucleus of the amygdala had a similar effect in reducing the increase in ethanol self-administration associated with acute withdrawal, suggesting a role for CRF2 receptors opposite to that of CRF1 receptors in modulating ethanol intake in dependent animals (Funk and Koob, 2007). CRF antagonists injected intracerebroventricularly or systemically also blocked the potentiated anxiety-like responses to stressors observed during protracted abstinence (Breese et al., 2005; Valdez et al., 2003) and the increased ethanol self-administration associated with protracted abstinence (Valdez et al., 2004; Funk et al., 2006). None of the CRF antagonists had any effects on ethanol self-administration in nondependent rats (Valdez et al., 2004). These data suggest an important role for CRF, primarily within the central nucleus of the amygdala, in mediating the increased self-administration associated with dependence.

Figure 3 
Effect of CRF1 Receptor Antagonist on Alcohol and Nicotine Self-Administration in Dependent Rats

Increased expression of CRF1 receptors is associated with stress-induced ethanol intake in Marchigian Sardinian (msP) alcohol-preferring rats (Hansson et al., 2006) as well as in nongenetically selected animals in a postdependent state (Sommer et al., 2008). In the genetically selected msP rat line, high ethanol preference was correlated with a genetic polymorphism of the crhr1 promoter and an increase in CRF1 density in the amygdala as well as increased sensitivity to stress and increased sensitivity to a CRF1 antagonist (Hansson et al., 2006). In nongenetically selected rats exposed to repeated cycles of ethanol intoxication and dependence, a CRF1 antagonist blocked the increased ethanol intake associated with protracted abstinence, an effect that coincided with upregulation of the CRF1 gene and downregulation of the CRF2 gene in the amygdala (Sommer et al., 2008). Adolescents homozygous for the C allele of R1876831 located on an intron that could potentially influence transcription of the CRF1 receptor gene drank more alcohol per occasion and had higher lifetime rates of heavy drinking in relation to negative life events than subjects carrying the T allele (Blomeyer et al., 2008). These results suggest the exciting possibility that certain single-nucleotide polymorphisms in the human population may predict vulnerability to certain subtypes of excessive drinking syndromes and, perhaps more exciting, may predict responsiveness to the use of CRF receptor antagonists in the treatment of alcoholism.

Similar interactions with CRF have been observed with the dependence associated with cocaine, heroin, and nicotine. Chronic administration of cocaine produces an anxiety-like response that is blocked by intracerebroventricular administration of a CRF1/CRF2 antagonist (Sarnyai et al., 1995; Basso et al., 1999). A CRF1/CRF2 peptide antagonist injected into the central nucleus of the amygdala and systemic administration of CRF1 antagonists blocked conditioned place aversion associated with precipitated opiate withdrawal (Heinrichs et al., 1995; Stinus et al., 2005). Opioid withdrawal also increased CRF release in the amygdala, measured by in vivo microdialysis (Weiss et al., 2001). CRF1 knockout mice failed to show conditioned place aversion to opioid withdrawal and failed to show an opioid-induced increase in dynorphin mRNA in the nucleus accumbens (Contarino and Papaleo, 2005). A CRF antagonist injected intracerebroventricularly blocked the anxiogenic-like effects of withdrawal from bolus injections of nicotine (Tucci et al., 2003). The anxiogenic-like effects of precipitated withdrawal from chronic nicotine also were blocked by a CRF1 receptor antagonist (George et al., 2007) (Figure 2). A CRF1/CRF2 peptide antagonist also blocked the nicotine withdrawal-induced increase in brain reward thresholds (Bruijnzeel et al., 2007). Continuous access to intravenous self-administration of cocaine for 12 hr, precipitated opioid withdrawal, and precipitated nicotine withdrawal increased CRF release in the amygdala during the withdrawal, measured by in vivo microdialysis (Richter and Weiss, 1999; Weiss et al., 2001; George et al., 2007) (Figure 2). Systemic administration of CRF1 antagonists reversed the increased self-administration of cocaine, heroin, and nicotine associated with extended access (Specio et al., 2008; George et al., 2007; T.N. Greenwell, C.K. Funk, P. Cottone, H.N. Richardson, S.A. Chen, K. Rice, M.J. Lee, E.P. Zorrilla, and G.F.K., unpublished data).

The role of CRF in stress-induced reinstatement of drug seeking follows a pattern of results similar to its role in the anxiety-like effects of acute withdrawal and dependence-induced increases in drug intake (for reviews, see Shaham et al., 2003; Lu et al., 2003) (Figure 1B). Mixed CRF1/CRF2 antagonists injected intracerebroventricularly and/or CRF1 small-molecule antagonists blocked stress-induced reinstatement of cocaine, opiate, alcohol, and nicotine intake (Erb et al., 1998; Lu et al., 2001; Shaham et al., 1997, 1998; Shalev et al., 2006; Le et al., 2000; Liu and Weiss, 2002; Gehlert et al., 2007; Hansson et al., 2006; Zislis et al., 2007). These effects have been replicated with intracerebral injections of a mixed CRF1/CRF2 antagonist or small-molecule CRF1 antagonist into the bed nucleus of the stria terminalis, median raphe, and ventral tegmental area, but not the amygdala or nucleus accumbens (Le et al., 2002; Erb et al., 2001; Erb and Stewart, 1999; Wang et al., 2006, 2007), suggesting that different sites, such as the bed nucleus of the stria terminalis, median raphe, and ventral tegmental area, may be important for stress-induced relapse, in contrast to the role of CRF in dependence-induced drug self-administration that has been localized to the central nucleus of the amygdala (Funk et al., 2006).

In summary, the extrahypothalamic CRF systems play a role in mediating the anxiety-like effects of acute withdrawal, the increase in drug-taking associated with dependence, and stress-induced reinstatement for all major drugs of abuse, including psychostimulants, opioids, ethanol, nicotine, and (with limited studies) cannabinoids. Many of these effects have been localized to the extended amygdala, and acute withdrawal from all major drugs of abuse increased CRF release in the central nucleus of the amygdala, measured by in vivo microdialysis (Figures 1B and ​and2).2). This pattern of results suggests a major role for CRF in mediating the negative emotional states that have motivational significance in maintaining the dependent state (Koob and Le Moal, 2005; Bruijnzeel and Gold, 2005).

2.2. Norepinephrine

Norepinephrine is a well established neurotransmitter in the central nervous system with widespread distribution throughout the brain (Figure 4) and has hypothesized functions in arousal, attention, stress, anxiety, and affective disorders (see Supplemental Data). Cell bodies for the brain norepinephrine systems originate in the dorsal pons and brainstem. The locus coeruleus in the dorsal pons is the source of the dorsal noradrenergic pathway to the cortices and hippocampus, and the brainstem projections converge in the ventral noradrenergic bundle to innervate the basal forebrain and hypothalamus.

Figure 4 
Localizations and Projections of Brain Stress Systems—Norepinephrine

Norepinephrine binds to three distinct families of receptors—α1, α2, and β-adrenergic—each with three receptor subtypes (Rohrer and Kobilka, 1998). The α1 receptor family comprises α1a, α1b, and α1d. Each subtype activates phospholipase C and α2 and are coupled to the inositol phosphate second messenger system via the G protein Gq. A centrally active α1 receptor antagonist used in drug dependence research is prazosin. The α2 family comprises α2a, α2b, and α2c. Each subtype inhibits adenylate cyclase via coupling to the inhibitory G protein Gi. Two α2 drugs commonly used in drug-dependence research are the α2 agonist clonidine and the α2 antagonist yohimbine. Because the α2 receptor is hypothesized to be presynaptic, these drugs inhibit and facilitate noradrenergic function, respectively. The β-adrenergic receptor family comprises β1, β2, and β3. Each subtype activates adenylate cyclase via coupling to the G protein Gs. Few β-adrenergic drugs have been explored in drug-dependence research, with the exception of the β-adrenergic antagonist propranolol, presumably because of poor brain bioavailability.

Precipitated morphine withdrawal increases norepinephrine release in the central nucleus of the amygdala and bed nucleus of the stria terminalis (Watanabe et al., 2003; Fuentealba et al., 2000). The noradrenergic α2 agonist clonidine, a functional norepinephrine antagonist with presynaptic actions, blocked the suppression in responding for food during opioid withdrawal, a measure of the motivational component of opioid withdrawal (Sparber and Meyer, 1978) and the aversive stimulus effects (conditioned place aversions) of opioid withdrawal (Schulteis et al., 1998). Increased anxiety-like behavior was observed during cocaine and morphine withdrawal in rats and was blocked by the β-adrenergic antagonists propranolol and atenolol (Harris and Aston-Jones, 1993; Gold et al., 1980). Similar effects were observed with direct injections of a β-adrenergic antagonist directly into the central nucleus of the amygdala (Rudoy and van Bockstaele, 2007). Norepinephrine functional antagonists (β1 antagonist and α2 agonist) injected into the lateral bed nucleus of the stria terminalis blocked precipitated opiate withdrawal-induced place aversions (Delfs et al., 2000), and β-adrenergic antagonists produced similar effects when injected into the central nucleus of the amygdala (Watanabe et al., 2003). Studies that further localized the effects of norepinephrine in driving opioid withdrawal showed that ventral noradrenergic bundle lesions attenuated opioid withdrawal (Delfs et al., 2000), but virtually complete lesions of the dorsal noradrenergic bundle from the locus coeruleus with the neurotoxin 6-hydroxydopamine failed to block the place aversion produced by opioid withdrawal-induced place aversion (Caille et al., 1999). Consistent with the studies of the aversive effects of opioid withdrawal, the α1 norepinephrine antagonist prazosin reduced heroin self-administration in dependent rats with extended access (Greenwell et al., 2008). Prazosin also selectively blocked the increased motivation to intravenously self-administer cocaine on a progressive-ratio schedule in rats with extended access to the drug (a procedure that is hypothesized to produce dependence) (Wee et al., 2008). The extended-access rats showed a decreased number of neurons with α1 adrenergic-like immunoreactivity in the bed nucleus of the stria terminalis, suggesting that the α1 noradrenergic system in the bed nucleus of the stria terminalis also may be involved in cocaine dependence (Wee et al., 2008).

Substantial evidence also has accumulated suggesting that, in animals and humans, central noradrenergic systems are activated during acute withdrawal from ethanol and may have motivational significance. Alcohol withdrawal in humans is associated with activation of noradrenergic function, and the signs and symptoms of alcohol withdrawal in humans are blocked by postsynaptic β-adrenergic blockade (Romach and Sellers, 1991). Alcohol withdrawal signs also are blocked in animals by administration of α1 antagonists and β-adrenergic antagonists and selective blockade of norepinephrine synthesis (Trzaskowska and Kostowski, 1983). In dependent rats, the α1 antagonist prazosin selectively blocked the increased drinking associated with acute withdrawal (Walker et al., 2008). Thus, converging data suggest that disruption of noradrenergic function blocks ethanol reinforcement, that noradrenergic neurotransmission is enhanced during ethanol withdrawal, and that noradrenergic functional antagonists can block aspects of ethanol withdrawal.

Chronic nicotine self-administration (23 hr access) increases norepinephrine release in the paraventricular nucleus of the hypothalamus and the amygdala, measured by in vivo microdialysis (Fu et al., 2001, 2003). However, during the late maintenance phase of 23 hr access to nicotine, norepinephrine release was no longer elevated in the amygdala, suggesting some desensitization/tolerance-like effect (Fu et al., 2003).

The role of norepinephrine in stress-induced reinstatement also follows a pattern of results similar to its role in the anxiety-like effects of acute withdrawal and dependence-induced increases in drug intake (for reviews, see Shaham et al., 2003; Lu et al., 2003). The α2 adrenergic agonist clonidine decreased stress-induced reinstatement of cocaine, opiate, alcohol, and nicotine seeking (Le et al., 2005; Erb et al., 2000; Shaham et al., 2000; Zislis et al., 2007). The α2 antagonist yohimbine reinstated drug seeking (Lee et al., 2004). Limited studies with intracerebral injections also have localized the effects of functional blockade of norepinephrine system on stress-induced reinstatement of morphine conditioned place preferences to the bed nucleus of the stria terminalis (Wang et al., 2001). β-adrenergic antagonists administered systemically also blocked stress-induced reinstatement of cocaine seeking (Leri et al., 2002).

2.3. Dynorphin/κ Opioid System

Dynorphins are opioid peptides that derive from the prodynorphin precursor and contain the leucine (leu)-enkephalin sequence at the N-terminal portion of the molecule and are the presumed endogenous ligands for the κ opioid receptor (Chavkin et al., 1982). Dynorphins have widespread distribution in the central nervous system (Watson et al., 1982) (Figure 5) and play a role in a wide variety of physiological systems, including neuroendocrine regulation, pain regulation, motor activity, cardiovascular function, respiration, temperature regulation, feeding behavior, and stress responsivity (Fallon and Leslie, 1986) (see Supplemental Data). Possible products of prodynorphin processing include dynorphin A(1-17), dynorphin A(1-8), and dynorphin B(1-29). Immunocytochemical distribution of dynorphin A and -B shows significant cell bodies and terminals in addiction-relevant brain areas such as the nucleus accumbens, central nucleus of the amygdala, bed nucleus of the stria terminalis, and hypothalamus (Fallon and Leslie, 1986). Dynorphins bind to all three opioid receptors but show a preference for κ receptors (Chavkin et al., 1982). Activation of the dynorphin/κ receptor system produces actions similar to other opioids but often actions that are opposite to those of μ opioid receptors in the motivational domain, in which dynorphins produce aversive dysphoric-like effects in animals and humans (Shippenberg et al., 2007).

Figure 5 
Localizations and Projections of Brain Stress Systems—Dynorphin

Dynorphin has long been hypothesized to mediate negative emotional states. κ receptor agonists produce place aversions (Shippenberg et al., 2007) and depression and dysphoria in humans (Pfeiffer et al., 1986). The activation of dynorphin systems in the nucleus accumbens has long been associated with activation of the dopamine systems by cocaine and amphetamine. Activation of dopamine D1 receptors stimulates a cascade of events that ultimately leads to cAMP response-element binding protein (CREB) phosphorylation and subsequent alterations in gene expression, notably the activation of expression of protachykinin and prodynorphin mRNA. The subsequent activation of dynorphin systems could contribute to the dysphoric syndrome associated with cocaine dependence and also feedback to decrease dopamine release (Nestler, 2005). Activation of dynorphin systems also may mediate a dysphoric component of stress (Land et al., 2008; McLaughlin et al., 2003).

The evidence for a role of the dynorphin/κ opioid system in the neuroadaptive actions of other drugs of abuse is based both on biochemical and antagonist studies. Substantial evidence suggests that dynorphin peptide and gene expression are activated in the striatum, ventral striatum, and amygdala during acute and chronic administration of cocaine and alcohol (Spangler et al., 1993; Daunais et al., 1993; Lindholm et al., 2000). Chronic binge patterns of cocaine administration increase μ and κ opioid receptor density in the nucleus accumbens, cingulate cortex, and basolateral amygdala (Unterwald et al., 1994).

A highly selective κ agonist, when administered chronically via minipump, potentiated the alcohol deprivation effect in rats with long-term ethanol experience, but acute injection of a κ antagonist had no effect, suggesting the possibility that ethanol drinking may be an attempt to overcome the aversive effects of κ agonists (Holter et al., 2000). Direct support for the hypothesis that dynorphin is part of the negative emotional systems recruited in dependence is the observation that nor-binaltorphimine, when injected intracerebroventricularly or systemically, blocked ethanol self-administration in dependent but not in non-dependent animals (Walker and Koob, 2008; B.M. Walker and G.F.K., unpublished data). κ knockout mice also drank less ethanol in a two-bottle choice test using escalating doses of ethanol (Kovacs et al., 2005).

Opiate withdrawal has been shown to increase dynorphin levels in the amygdala (Rattan et al., 1992) and nucleus accumbens (Turchan et al., 1997). Animals with a history of heroin self-administration showed increased levels of dynorphin A and -B in the striatum at a time point just before the next scheduled self-administration session (Cappendijk et al., 1999). Intracerebroventricular dynorphin A treatment decreased heroin-stimulated dopamine release and significantly increased heroin self-administration in daily 5 hr sessions, whereas a κ antagonist had the opposite effects (Xi et al., 1998).

Stress increases dynorphin activity, suggesting a potential interaction with CRF systems. Blockade of dynorphin activity, either via κ receptor antagonism or prodynorphin gene disruption, blocked stress-induced reinstatement of cocaine-induced place preference in mice (McLaughlin et al., 2003) and blocked stress-induced reinstatement of cocaine-seeking behavior (Beardsley et al., 2005). Forced swim stress and inescapable footshock produced place aversions in mice that were blocked by a κ antagonist and dynorphin knockout, and here, CRF was hypothesized to produce its aversive effect via a CRF2 receptor-dynorphin interaction (Land et al., 2008). Evidence also exists showing that reinstatement of drug-seeking behavior via activation of κ opioid receptors is mediated by CRF, and κ agonist-induced reinstatement of cocaine seeking was blocked by a CRF1 antagonist (Valdez et al., 2007). Thus, the dynorphin/κ system mimics stressor administration in animals in producing aversive effects and inducing drug-seeking behavior, and this aversive response may involve reciprocal interactions with nucleus accumbens dopamine and the brain extrahypothalamic CRF system.

2.4. Orexin

Orexin (also known as hypocretin)-containing neurons derive exclusively from the lateral hypothalamus and project widely throughout the brain (Peyron et al., 1998), with a dense innervation of anatomical sites involved in regulating arousal, motivation, and stress states (Baldo et al., 2003) (Figure 6) (see Supplemental Data). Orexin A and orexin B have actions that are mediated by two G protein-coupled receptors, OX1 and OX2 (also referred to as hypocretin 1 and -2, respectively, but orexin A, orexin B, OX1, and OX2 are the accepted International Union of Pharmacology nomenclature). OX1 has higher affinity for orexin A, and OX2 has equal affinity for both orexin A and -B (Sakurai et al., 1998). The orexin neuropeptides orexin A and orexin B interact with noradrenergic, cholinergic, serotonergic, histaminergic, and dopaminergic systems, in addition to the HPA axis, to mediate sleep-wake regulation, energy homeostasis, and motivational, neuroendocrine, and cardiovascular functions (Sutcliffe and de Lecea, 2002).

Figure 6 
Localizations and Projections of Brain Stress Systems—Orexin (Hypocretin)

A role for the orexin systems in the neuroadaptive processes linked to dependence have been hypothesized based on a brain arousal-stress function. Orexin neurons have been implicated in drug seeking. Orexin neurons in the lateral hypothalamus are activated by cues associated with rewards, such as food or drugs, and exogenous stimulation of lateral hypothalamic orexin neurons reinstates extinguished drug-seeking behavior in rodents (Harris et al., 2005). Injection of an OX1 antagonist decreased the place preference produced by morphine (Narita et al., 2006).

Using an intravenous cocaine self-administration model, administration of orexin A reinstated previously extinguished cocaine-seeking behavior, but rather than potentiating reward, orexin A induced a long-lasting brain reward deficit (Boutrel et al., 2005). The reinstatement of cocaine-seeking behavior by orexin also was blocked by noradrenergic or CRF receptor antagonists. Antagonism of OX1 receptors prevented footshock-induced reinstatement of cocaine-seeking behavior in rats (Boutrel et al., 2005). Additionally, footshock stress elicited a selective effect on activation of orexin neurons in the perifornical-dorsomedial hypothalamus, leading to the hypothesis that orexin neurons in the lateral hypothalamus mediate reward activation/arousal, whereas orexin neurons in the perifornical-dorsomedial hypothalamus mediate stress activation/arousal/memory (Harris and Aston-Jones, 2006). Orexin A, possibly from the perifornical-dorsomedial hypothalamus, activates CRF-expressing neurons in the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala (Sakamoto et al., 2004). CRF neurons innervate orexin neurons, possibly from the extended amygdala (Winsky-Sommerer et al., 2004), suggesting a novel reciprocal stress-activation system. Overall, these results suggest a dynamic relationship between orexin and reward/stress pathways in regulating the reinstatement of previously extinguished drug-seeking behaviors. Studies on the role of specific orexin peptide receptors and specific brain sites on the motivational aspects of drug dependence remain to be explored.

2.5. Vasopressin

The neurohypophysial peptide vasopressin has actions in the central nervous system in addition to its classic role as an antidiuretic hormone derived from the posterior pituitary (see Supplemental Data). Vasopressin is widely distributed in the brain outside of the hypothalamus, and the highest vasopressin concentrations are in the suprachiasmatic and supraoptic nuclei, but substantial levels also have been observed in the septum and locus coeruleus (Figure 7). Vasopressin neurons innervating the extended amygdala are hypothesized to derive from cell bodies in the medial bed nucleus of the stria terminalis (de Vries and Miller, 1998). Vasopressin binds to three different G protein-coupled receptor subtypes: V1a, V1b, and V2. The V2 receptor is expressed almost exclusively in the kidney, where it mediates the antidiuretic action of vasopressin. The V1a and V1b receptors are localized to the brain, and the distribution of vasopressin receptor binding is prominent in the rat extended amygdala, with high concentrations in the lateral and supracapsular bed nucleus of the stria terminalis, the central nucleus of the amygdala, and the shell of the nucleus accumbens (Veinante and Freund-Mercier, 1997).

Figure 7 
Localizations and Projections of Brain Stress Systems—Vasopressin

Vasopressin mRNA levels were increased selectively in the amygdala during early spontaneous withdrawal from heroin, and a selective V1b receptor antagonist, SSR149415, blocked footshock-induced reinstatement of heroin-seeking behavior, suggesting that vasopressin systems in the amygdala may be a key component of the aversive emotional consequences of opioid withdrawal (Zhou et al., 2008). Prolonged or chronic ethanol exposure decreased vasopressin-like immunoreactivity in the hypothalamus and the bed nucleus of the stria terminalis projection to the lateral septum (Gulya et al., 1991). A selective V1b receptor antagonist dose-dependently blocked the increase in ethanol self-administration during withdrawal in dependent rats but had no effect in nondependent animals (S. Edwards et al., 2008, Soc. Neurosci., abstract). To date, few studies have explored the motivational effects of vasopressin antagonists in animal models of dependence or stress-induced reinstatement with other drugs of abuse. However, the literature suggesting that V1b antagonists have anxiolytic-like profiles (see Supplemental Data) and that vasopressin and its receptors are highly expressed in the extended amygdala lends credence to the hypothesis that vasopressin systems in the extended amygdala may have a role in the increased alcohol intake associated with dependence.

3. Brain Antistress Systems and Addiction: Neuropeptide Y and Nociceptin

3.1. Neuropeptide Y

Neuropeptide Y (NPY) is a 36 amino acid polypeptide with powerful orexigenic and anxiolytic-like actions (see Supplemental Data). NPY is distributed widely throughout the central nervous system but with high concentrations in the extended amygdala (Adrian et al., 1983) (Figure 8). Multiple NPY receptor subtypes have been identified, with the Y1 and Y2 subtypes most implicated in stress and drug actions. The Y1 receptor has a wide distribution throughout the rat brain, where it is most abundantly found in the cortex, olfactory tubercle, hippocampus, hypothalamus, and thalamus (Parker and Herzog, 1999). The distribution of Y2 receptors is similar to that of Y1 receptors, although Y2 receptor expression is less abundant in the cortex and thalamus and more abundant in the hippocampus (Parker and Herzog, 1999). Y1 receptors are hypothesized to be postsynaptic and Y2 receptors presynaptic (Heilig and Thorsell, 2002).

Figure 8 
Localizations and Projections of Brain Antistress Systems—Neuropeptide Y

NPY administered intracerebroventricularly blocked ethanol withdrawal (Woldbye et al., 2002). Subsequent studies using animal models of dependence-induced drinking in rodents showed that NPY administered intracerebroventricularly reduced limited-access alcohol intake in Wistar rats if they had a history of alcohol dependence produced by chronic intermittent exposure to alcohol vapor (Thorsell et al., 2005). Intracerebroventricularly administered NPY also suppressed alcohol intake in rats selectively bred for high alcohol preference but did not alter alcohol intake in their low alcohol-preferring counterparts (Badia-Elder et al., 2001, 2003). The suppressive effects of intracerebroventricularly administered NPY on ethanol drinking in P rats is enhanced and prolonged following periods of imposed alcohol abstinence (Gilpin et al., 2003). Intracerebroventricular administration of NPY did not affect limited-access nondependent alcohol intake by Wistar rats (Badia-Elder et al., 2001).

Given the evidence that the anti-anxiety-like effects of NPY are mediated by the central or basolateral amygdala complex (Heilig et al., 1994), a logical site for exploring the NPY-induced decrease in excessive ethanol intake is the central nucleus of the amygdala. Ethanol withdrawal decreased NPY protein in the central and medial nuclei of the amygdala (Roy and Pandey, 2002). Infusion of a viral vector encoding prepro-NPY directly into the central nucleus of the amygdala reduced continuous-access alcohol drinking by Long-Evans rats that exhibited anxiety-like behavior in the elevated plus maze (Primeaux et al., 2006). In Wistar rats with a history of dependence and multiple abstinence periods, viral vector-induced amygdala NPY overexpression reduced anxiety-like behavior and produced long-term suppression of alcohol drinking (Thorsell et al., 2007). In P rats with a long history of alcohol consumption, infusions of NPY directly into the central nucleus of the amygdala suppressed alcohol drinking only in P rats that were subjected to periods of imposed alcohol abstinence (Gilpin et al., 2008). P rats have been shown to have lower basal levels of NPY in the central nucleus of the amygdala and correlationally higher anxiety-like behavior compared with alcohol-nonpreferring rats (Suzuki et al., 2004; Pandey et al., 2005). Increases in NPY activity in the central nucleus of the amygdala, produced via alterations in CREB function or direct administration of NPY, decreased ethanol intake and anxiety-like behavior in P rats with a short history of self-administration (Pandey et al. 2005). Exogenous NPY administered into the central nucleus of the amygdala also significantly decreased alcohol drinking by alcohol-dependent rats but not in nondependent controls (Gilpin et al., 2008), confirming the results observed with viral vector-induced induction of NPY activity (Thorsell et al., 2007).

Both Y1 and Y2 receptor subtypes are involved in the excessive drinking associated with alcohol dependence. Y1 receptor knockout mice show increased alcohol consumption (Thiele et al., 2002). In contrast, Y2 receptor knockout mice drink significantly less alcohol (Thiele et al., 2004). Pharmacological studies have confirmed that blockade of Y1 receptors increases ethanol intake in C57BL/6 high-drinking mice (Sparta et al., 2004) and blockade of Y2 receptors decreases ethanol intake in dependent animals (Rimondini et al., 2005) and in animals responding for ethanol in a sweet solution (Thorsell et al., 2002). Y1 knockout mice and Y1 antagonists show an anxiogenic-like profile, and Y2 knockout mice and Y2 antagonists show an anxiolytic-like profile, thus providing an important link between the NPY system, anxiety-like responses, and alcohol intake in dependent animals (Valdez and Koob, 2004). Combined with the extensive work in dependent animals, these studies suggest that the NPY system may change its impact on drinking during the transition from nondependent to dependent drinking.

These studies suggest that both constitutive and alcohol-induced changes in NPY activity in the amygdala may be involved not only in mediating anxiety-like responses but also in the motivational effects of ethanol dependence. One hypothesis is that decreased activity of NPY, parallel to increased activity of CRF, may provide a motivational basis for increased alcohol self-administration during alcohol withdrawal or protracted abstinence that drives excessive alcohol consumption (Heilig et al., 1994).

NPY has been implicated in dependence on other drugs of abuse, but the extant literature is not as extensive. Chronic heroin treatment increased NPY neuron activity measured by immunohistochemistry in the thalamic paraventricular nucleus and bed nucleus of the stria terminalis (D’Este et al., 2006). NPY administered intracerebroventricularly blocked the somatic signs of withdrawal from morphine precipitated by the opioid antagonist naloxone, and these behavioral changes were accompanied by decreases in c-fos expression in the locus coeruleus, lateral septal nucleus, periaqueductal gray, cingulate and frontal cortices, and septohippocampal nucleus (Clausen et al., 2001). NPY and NPY peptide analogs administered intracerebroventricularly decreased naloxone-precipitated withdrawal in rats (Woldbye et al., 1998).

3.2. Nociceptin (Orphanin FQ)

Nociceptin is the endogenous ligand for the nociceptin/orphanin FQ peptide (NOP) receptor (the accepted International Union on Pharmacology nomenclature; the receptor also has been referred to as the orphan opioid receptor or opioid receptor-like-1, or ORL-1 receptor) (Mollereau et al., 1994). Nociceptin is a 17 amino acid polypeptide structurally related to the opioid peptide dynorphin A (Reinscheid et al., 1995; Meunier et al., 1995). Nociceptin does not bind to μ, δ, or κ receptors, and no known opioids bind to the NOP receptor. Brain mapping studies have shown that the neuroanatomical distribution of nociceptin and its receptor are distinct from those of other opioid peptides and probably represent local short projection circuits (Neal et al., 1999) (Figure 9). The highest density of nociceptin and its receptor can be found in the cortex, amygdala, bed nucleus of the stria terminalis, medial prefrontal cortex, ventral tegmental area, lateral hypothalamus, nucleus accumbens, and many brainstem areas, including the locus coeruleus and raphe (Darland et al., 1998; Neal et al., 1999).

Figure 9 
Localizations and Projections of Brain Antistress Systems—Nociceptin/Orphanin FQ

NOP receptor agonists, antagonists, and knockouts have numerous functional effects, including blocking stress-induced analgesia, anxiolytic-like effects, and drug reward (see Supplemental Data). Consistent with the role of nociceptin in stress-related responses, the nociceptin system also may modulate dependence via actions on brain emotional systems involved in the brain stress responses. Intracerebroventricular treatment with nociceptin (Ciccocioppo et al., 1999, 2004) or peptidic NOP receptor agonists (Economidou et al., 2006) significantly decreased ethanol consumption in msP rats. These effects were blocked by a nociceptin antagonist (Ciccocioppo et al., 2003). However, NOP knockout mice backcrossed onto a C57BL/6 background also showed decreases in ethanol consumption in a two-bottle choice test (Sakoori and Murphy, 2008), and certain regimens of NOP receptor agonist administration increased ethanol intake (Economidou et al., 2006).

Nociceptin significantly reduced stress-induced reinstatement of ethanol- (but not cocaine-) seeking behavior in Wistar rats (Martin-Fardon et al., 2000) and cue-induced reinstatement in msP rats (Ciccocioppo et al., 2003). In addition, activation of the NOP receptor inhibited drug-induced reinstatement of ethanol- and morphine-induced conditioned place preference in mice (Kuzmin et al., 2003; Shoblock et al., 2005) and prevented relapse-like behavior in the alcohol deprivation model in msP rats (Kuzmin et al., 2007).

Thus, activation of the nociceptin system decreased the acute rewarding effects of drugs of abuse measured by place preference, produced antistress effects, blocked ethanol consumption in a genetically selected line known to be hypersensitive to stressors, and decreased reinstatement of drug-seeking behavior. Investigating the role of nociceptin in dependence-induced drinking and the localization of its site of action for its effects on drinking remains for future work.

4. Cellular Mechanisms of the Brain Stress Systems in the Extended Amygdala

Elements of the brain stress and antistress systems can be hypothesized to act in series or in parallel on common mechanisms in the extended amygdala to affect emotional states. Cellular studies using electrophysiological techniques have the power to elucidate the common mechanisms. To date, most studies have explored either γ-aminobutyric acid (GABA) or glutamatergic activity within the extended amygdala, and some parallels can be found at the cellular level that appear at the behavioral-neuropharmacological level of analysis.

In the amygdala, CRF is localized within a subpopulation of GABAergic neurons in the bed nucleus of the stria terminalis and central nucleus of the amygdala that are different from those that colocalized with enkephalin (Day et al., 1999). In brain slice preparations, CRF enhanced GABAA inhibitory postsynaptic potentials (IPSCs) in whole-cell recordings of the central nucleus of the amygdala, and this effect was blocked by CRF1 antagonists and in CRF1 knockout mice (Nie et al., 2004). Nociceptin had the opposite effects in the central nucleus of the amygdala—decreasing GABAergic IPSCs (Roberto and Siggins, 2006). Vasopressin also activated cells in the medial part of the central nucleus of the amygdala (Huber et al., 2005). These results show that CRF and vasopressin, which are anxiogenic-like, activate GABAergic interneurons in the central nucleus of the amygdala.

Most neurons in the central nucleus of the amygdala are GABAergic, either inhibitory interneurons with recurrent or feed-forward connections or inhibitory projection neurons to brainstem or downstream regions (e.g., bed nucleus of the stria terminalis). The central nucleus of the amygdala can be identified as a “gate” that regulates the flow of information through the intra-amygdaloidal circuits, and the fine-tuning of the GABAergic inhibitory system in the central nucleus of the amygdala may be a prerequisite for controlling both local and output neurons to downstream nuclei. Because GABAergic drugs are typically robust anxiolytics, the fact that anxiogenic-like neurotransmitters would activate GABAergic neurotransmission and anxiolytic-like neurotransmitters would depress GABAergic transmission in a brain region known to be involved in stress-related behavior may seem paradoxical. However, local GABAergic activity within the central nucleus of the amygdala may functionally influence neuronal responsivity of inhibitory central nucleus of the amygdala gating that regulates information flow through the local intra-amygdaloidal circuits (i.e., by disinhibiting the central nucleus of the amygdala), leading to increased inhibition in downstream regions that mediate the behavioral response.

In the bed nucleus of the stria terminalis, whole-cell recordings from slice preparations demonstrated that CRF enhanced GABAergic neurotransmission, and the CRF effect appeared to be via the CRF1 receptor similar to the effects in the amygdala, and NPY inhibited GABAergic neurotransmission (Kash and Winder, 2006). The predominant noradrenergic innervation of the bed nucleus of the stria terminalis is in the ventral part, and here norepinephrine decreases glutamatergic activity measured both electrophysiologically and with in vivo microdialysis (Egli et al., 2005; Forray et al., 1999). Norepinephrine also increased GABAA IPSCs (Dumont and Williams, 2004). Thus, if one combines the data from the central nucleus of the amygdala and the bed nucleus of the stria terminalis, then certain consistencies evolve (Table 3). CRF, vasopressin, and norepinephrine increase GABAergic activity, and NPY and nociceptin decrease GABAergic activity, actions at the cellular level that are parallel to the behavioral effects described above with neuropharmacological studies (Table 3).

Table 3 
Effects of Brain Stress Neurotransmitters on GABAergic Activity in the Extended Amygdala

Other researchers have argued that increasing excitability in the basolateral nucleus of the amygdala contributes to the anxiogenic-like effects of CRF (Rainnie et al., 2004). Using whole-cell patch-clamp recordings from basolateral amygdala neurons of animals chronically administered a CRF1/CRF2 agonist, urocortin, showed an N-methyl-D-aspartate (NMDA) receptor-mediated decrease in both spontaneous and stimulation-evoked IPSPs (Rainnie et al., 2004). Ethanol withdrawal, diazepam withdrawal, and uncontrollable stress also suppress IPSCs of the cells in the basolateral amygdala using a whole-cell patch-clamp preparation (Isoardi et al., 2007). These NMDA-mediated effects are the opposite of the GABA-mediated effects observed in the central nucleus of the amygdala and suggest that an integration of the role of the central and basolateral nuclei of the amygdala in stress and dependence responses will be required.

With the exception of recent studies with ethanol dependence, little work has been done at the cellular level in the extended amygdala on the changes in neurotransmission in the brain stress systems with the development of dependence. Chronic ethanol-induced changes in neuronal activity of GABA interneurons in the central nucleus of the amygdala have been linked to actions of CRF and nociceptin. Acute administration of doses of alcohol in the intoxicating range increased GABAA receptor-mediated IPSCs in central nucleus of the amygdala neurons, and this effect has been hypothesized to be attributable to an increase in presynaptic GABA release (Roberto et al., 2003; Nie et al., 2004). Even more striking is that the augmented GABA release is increased even further in dependent animals, shown both by electrophysiological and in vivo microdialysis measures (Roberto et al., 2004). The ethanol-induced enhancement of GABAergic IPSCs was blocked by CRF1 antagonists (Nie et al., 2004; Roberto et al., 2004) and was not observed in CRF1 knockout mice (Nie et al., 2004). Nociceptin-induced inhibition of IPSCs was increased in dependent animals, suggesting an increased sensitivity to nociceptin (Roberto and Siggins, 2006). Thus, not only do the brain stress/antistress systems interact systematically with the hypothesized GABAergic interneurons of the central nucleus of the amygdala, but ethanol dependence also sensitizes these neurons to the actions of the brain stress/antistress systems.

5. Neurocircuitry of the Brain Stress Systems in Dependence

Five potential arousal-stress neurotransmitter systems (CRF, norepinephrine, vasopressin, orexin, dynorphin) and two potential antistress neurotransmitter systems (NPY, nociceptin) have been explored in the present review from the perspective of a role in the neuroadaptation associated with the development of negative emotional states associated with drug dependence and addiction. The most compelling data are in the domain of CRF, where, for virtually all major drugs of abuse, (1) CRF is released during acute withdrawal, (2) CRF antagonists block the anxiogenic-like effects of acute withdrawal, (3) CRF antagonists block the excessive drug intake associated with dependence, and (4) CRF antagonists block stress-induced reinstatement. The focal point for most of these effects is the central nucleus of the amygdala and the bed nucleus of the stria terminalis (see Figure 1).

Although less extensive, similar data exist for some noradrenergic antagonists that block the anxiogenic-like effects of opiate withdrawal, block excessive drug intake associated with dependence on ethanol, cocaine, and opioids, and block stress-induced reinstatement to cocaine, opioids, ethanol, and nicotine (see Figure 4). Again, the focal point for many of these effects is the central nucleus of the amygdala and the bed nucleus of the stria terminalis.

Much evidence has been marshaled to show that dynorphin is increased in the nucleus accumbens in response to dopaminergic activation and, in turn, that overactivity of the dynorphin systems can decrease dopaminergic function. κ antagonists have been shown to block the aversive effects of drug withdrawal and the excessive drinking associated with ethanol dependence and stress-induced reinstatement of drug seeking (see Figure 5). Evidence suggests that κ receptor activation can produce CRF release (Song and Takemori, 1992), but recently some have argued that the effects of dynorphin in producing negative emotional states are mediated via activation of CRF systems (Land et al., 2008).

Much less evidence to date has demonstrated a direct role for vasopressin and orexin in the negative emotional states associated with drug dependence (see Figures 6 and ​and7).7). A vasopressin antagonist blocked stress-induced reinstatement of heroin-seeking behavior and withdrawal-induced ethanol drinking, and an orexin antagonist blocked stress-induced reinstatement of cocaine seeking. Much more work will be required to explore the role of these systems and their interactions with other major players, such as CRF.

Significant evidence suggests that activation of NPY in the central nucleus of the amygdala can block the motivational aspects of dependence associated with chronic ethanol administration. NPY administered intracerebroventricularly blocked the anxiogenic-like effects of withdrawal from ethanol and blocked the increased drug intake associated with ethanol dependence (see Figure 8). Direct administration or viral vector-enhanced expression of NPY into the central nucleus of the amygdala also blocked the increased drug intake associated with ethanol dependence. Few or no studies have examined the effects of NPY on motivational aspects of dependence with other drugs of abuse.

The role for nociceptin in dependence suggests interactions both with the rewarding effects of drugs of abuse and in the motivational aspects of dependence, mainly with ethanol. Nociceptin blocks the rewarding effects of most major drugs of abuse measured by place preference (see Supplemental Data). Nociceptin decreased ethanol self-administration in msP rats known to have a constitutive increase in CRF activity and a stress-like phenotype. msP rats are known to have a high basal stress response, to show decreased ethanol intake similar to dependent rats with administration of a CRF1 antagonist, and to carry a genetic polymorphism of the CRF1 promoter, resulting in increased CRF1 density in several brain regions (Hansson et al., 2006) (see Figure 9). Nociceptin also significantly reduced stress-induced reinstatement of ethanol. Future studies should explore the role of both of these antistress systems (NPY, nociceptin) in the negative emotional responses associated with dependence on other drugs of abuse.

A pronounced interaction exists between central nervous system CRF and norepinephrine systems. Conceptualized as a feed-forward system at multiple levels of the pons and basal forebrain, CRF activates norepinephrine, and norepinephrine in turn activates CRF (Koob, 1999; see Supplemental Data).

The common neurocircuitry actions of drugs of abuse on the brain stress systems and the change in plasticity of these circuits (see above) may involve molecular neuroadaptations that either differentially drive the circuits or result from the changes in activity of the circuits or both. Repeated perturbation of intracellular signal transduction pathways may cause changes in neuronal function and/or changes in nuclear function and altered rates of transcription of particular target genes. Altered expression of such genes would lead to presumably long-term altered activity of the neurons where such changes occur and ultimately to changes in neural circuits in which those neurons operate. Much work in addiction has shown that chronic exposure to opiods and cocaine leads to activation of CREB in the nucleus accumbens and central nucleus of the amygdala (Shaw-Lutchman et al., 2002; Edwards et al., 2007). Although acute administration of drugs of abuse can cause a rapid (within hours) activation of members of the Fos protein family, such as FosB, Fra-1, and Fra-2 in the nucleus accumbens, other transcription factors, isoforms of ΔFosB, have been shown to accumulate over longer periods of time (days) with repeated drug administration (Nestler, 2005). Animals with activated ΔFosB have exaggerated sensitivity to the rewarding effects of drugs of abuse, and ΔFosB may be a sustained molecular “switch” that helps to initiate and maintain a state of addiction (McClung et al., 2004). Whether (and how) such transcription factors influence the function of the brain stress systems, such as CRF and those described above, remains to be determined.

A focus of this review has been on the connections of the brain arousal-stress systems with the extended amygdala, particularly the central nucleus of the amygdala and the bed nucleus of the stria terminalis. Three of the seven systems (norepinephrine, orexin, NPY) are widely distributed in the brain but with a heavy innervation of the extended amygdala. Four of the systems (CRF, vasopressin, nociceptin, dynorphin) are more localized to local circuits throughout the forebrain but also with a heavy innervation of the extended amygdala (Figure 10). However, the convergence of these neurotransmitter systems in the region of the extended amygdala suggests key roles in the processing of emotional stimuli potentially triggered by neurons deriving from the brainstem (norepinephrine), hypothalamus (nociceptin, NPY), and within the extended amygdala itself (CRF, vasopressin, nociceptin, dynorphin). The extended amygdala receives afferents from the prefrontal cortex and insula and sends efferents to the lateral hypothalamus, ventral tegmental area, and pedunculopontine nucleus (Figure 10). Which parts of this neurocircuitry play a key role in the negative emotional states of drug dependence and how they interact with the brain stress systems remain to be elucidated. What is known is that most of the cells in the lateral division of the central nucleus of the amygdala and bed nucleus of the stria terminalis (extended amygdala) are GABAergic and that a distinct subpopulation colocalizes with either enkephalin or CRF, but they virtually never colocalize together on the same GABAergic cell (Day et al., 1999). Only enkephalin, and not CRF, colabeled neurons were activated by interleukin-1β, suggesting that discrete neural circuits exist within the extended amygdala (Day et al., 1999). Additionally, the electrophysiological anatomical studies outlined above suggest that these GABAergic neurons in the central nucleus of the amygdala respond to arousal-stress neurotransmitters with increased firing and respond to antistress neurotransmitters with decreased firing. These GABAergic neurons that are intrinsic to the central nucleus of the amygdala may be interneurons that inhibit another GABAergic link in the efferent pathway (Day et al., 1999; Davis et al., 1994).

Figure 10 
The Extended Amygdala and Its Afferent and Major Efferent Connections and Modulation via Brain Arousal-Stress Systems

The hypothesis that the central nucleus of the amygdala forms a focal point for a convergence of emotional stimuli to produce emotional responses has long been formulated for conditioned fear and pain. A cortexlateral amygdalacentral nucleus of the amygdala circuit has been shown to be critical for the expression of fear conditioning (Phelps and Le Doux, 2005). A conditioned acoustic stimulus activated the lateral nucleus of the lateral amygdala via auditory processing areas in the medial division of the medial geniculate body and auditory association cortex. The lateral amygdala, in turn, projects to the central amygdala, which controls the expression of fear responses through projections to the brainstem (Phelps and Le Doux, 2005).

Substantial evidence implicates the amygdala in both pain modulation and emotional responses to pain. In addition to receiving well-processed affective and cognitive inputs, pain-related information is conveyed to the lateral, basolateral, and central nuclei of the amygdala via both the spinothalamic and spinohypothalamic pain pathways but also via projections from the spino-parabrachial-amygdaloid pain pathway (spinal cord and trigeminal nucleus to the parabrachial nucleus and then to the central nucleus of the amygdala) (Bernard and Besson, 1990). Both of these pathways have been implicated in mediating the affective dimension of pain (Neugebauer et al., 2004). Numerous parallels may exist in amygdala mediation of the emotional dysregulation of addiction outlined above and the emotional component of pain mediated by the amygdala. These parallels include interactions between stress, depression, and pain (Neugebauer et al., 2004), the relationship between tolerance and sensitization to pain (Celerier et al., 2001), and the glucocorticoid modulation of pain (Greenwood-Van Meerveld et al., 2001). How the brain stress neurotransmitters outlined above play a role in both processes is a challenge for future research.

6. Hedonic Homeostatic Dysregulation as a Conceptual Framework for Linking Stress Systems and Addiction

6.1. Hypothalamic-Pituitary-Adrenal Axis as a Facilitator

As noted above, all drugs of abuse engage the HPA axis during acquisition of drug taking and again during acute withdrawal from the drug, and both CRF and vasopressin in the paraventricular nucleus of the hypothalamus control these responses. However, as the cycle of drug taking and withdrawal continues, the HPA axis response shows tolerance, but the repeated exposure of the brain to high levels of glucorticoids can continue to have profound effects on the extrahypothalamic brain stress systems. Strong evidence suggests that glucocorticoids “sensitize” the CRF system in the amygdala (Imaki et al., 1991; Makino et al., 1994; Swanson and Simmons, 1989). Thus, engagement of the brain stress systems may contribute to the negative emotional state that dissipates with time following a single injection of a drug, but with repeated administration of drug grows larger with time (or fails to return to normal homeostatic baseline), in contrast to the HPA axis, setting up a negative reinforcement mechanism (see also “Allostasis and Addiction” section below). Thus, the HPA axis and glucocorticoids are linked to high responsivity to novelty and facilitation of reward in initial drug use and also may be involved in potentiating adaptations in many parts of the neuraxis, particularly in extended amygdala systems where they contribute to the shift from homeostasis to pathophysiology associated with drug abuse. These results suggest that activation of the HPA component of stress can play an important role in facilitating both reward and brain stress neurochemical systems implicated in the development of addiction.

6.2. Opponent Process/Between-System Neuroadaptations

As defined above, opponent process, between-system neuroadaptations (Table 1) are hypothesized to involve activation of the neurotransmitter systems grouped together in this review as the brain arousal-stress systems. Thus, recruitment of the CRF system occurs during the development of dependence for all drugs of abuse that has motivational significance (Figure 1B above), but additional between-system neuroadaptations associated with motivational withdrawal include activation of the dynorphin/κ opioid system, norepinephrine brain stress system, extrahypothalamic vasopressin system, and possibly the orexin system. Additionally, activation of the brain stress systems may not only contribute to the negative motivational state associated with acute abstinence but also may contribute to the vulnerability to stressors observed during protracted abstinence in humans. However, brain antistress systems, such as NPY and nociceptin, also may be compromised during the development of dependence, thus removing a mechanism for restoring homeostasis (Koob and Le Moal, 2008). These results suggest that the motivation to continue drug use during dependence not only includes a change in the function of neurotransmitters associated with the acute reinforcing effects of drugs of abuse during the development of dependence, such as dopamine, opioid peptides, serotonin, and GABA, but also recruitment of the brain stress systems and/or disruption of the brain antistress systems (Koob and Le Moal, 2005).

The neuroanatomical entity integrating these brain arousal-stress and antistress systems may be the extended amygdala. Thus, the extended amygdala may represent a neuroanatomical substrate for the negative effects on reward function produced by stress that help drive compulsive drug administration (Koob and Le Moal, 2008) (Figure 10). The extended amygdala has a role in integrating emotional states such as the expression of the conditioned fear response in the central nucleus of the amygdala (Phelps and Le Doux, 2005) and emotional pain processing (Neugebauer et al., 2004) (see above). The integration of data from addiction neurobiology and from behavioral neuroscience of fear and pain point to a rich substrate for the integration of emotional stimuli related to the arousal-stress continuum (Pfaff, 2006) and provides insights not only into the mechanisms of emotional dysregulation in addiction but also into the mechanisms of emotions themselves.

The development of the aversive emotional state that drives the negative reinforcement of addiction is hypothesized to involve a long-term, persistent plasticity in the activity of neural circuits mediating motivational systems that derive from recruitment of antireward systems that drive aversive states. The withdrawal/negative affect stage defined above consists of key motivational elements, such as chronic irritability, emotional pain, malaise, dysphoria, alexithymia, and loss of motivation for natural rewards, and is characterized in animals by increases in reward thresholds during withdrawal from all major drugs of abuse. Antireward is a concept based on the hypothesis that brain systems are in place to limit reward (Koob and Le Moal, 1997, 2005, 2008). As dependence and withdrawal develop, brain antireward systems such as CRF, norepinephrine, dynorphin, vasopressin, and possibly orexin are hypothesized to be recruited to produce stress-like aversive states (Koob and Le Moal, 2001; Nestler, 2005; Aston-Jones et al., 1999) (Figure 10). The present thesis also argues that antistress systems, such as NPY and orexin that presumably buffer the stress response, also may be compromised. At the same time, decreases in reward function occur within the motivational circuits of the ventral striatum-extended amygdala (Figure 10). The combination of decreases in reward neurotransmitter function, recruitment of antireward systems, and compromised antistress systems provides a powerful source of negative reinforcement that contributes to compulsive drug-seeking behavior and addiction.

6.3. Stress Systems in Relapse

Although less developed except in studies with CRF and norepinephrine, the brain stress systems also may contribute to the critical problem in drug addiction of chronic relapse, where addicts return to compulsive drug taking long after acute withdrawal. The preoccupation/anticipation (craving) stage consists of two processes: protracted abstinence and stress-induced relapse. In animals, protracted abstinence can include increased sensitivity to a stressor or increased drug seeking long after acute withdrawal, both of which having been observed in alcohol studies (Valdez and Koob, 2004). Using CRF as an example in protracted abstinence, CRF is hypothesized to contribute to a residual negative emotional state that provides a basis for drug seeking (Valdez et al., 2002; Valdez and Koob, 2004).

Stress-induced reinstatement is robust and mediated by different elements of the same brain stress systems implicated in drug dependence, as noted above (for review, see Shaham et al., 2000, 2003). In stress-induced reinstatement, CRF systems in the bed nucleus of the stria terminalis are activated when acute stressors induce relapse (Shaham et al., 2003). CRF antagonists block stress-induced reinstatement of cocaine, alcohol, and opioid self-administration (Erb et al., 1998; Liu and Weiss, 2002; Shaham et al., 1998; Zislis et al., 2007). However, stress-induced reinstatement occurs independently of stress-induced activation of the HPA axis (Erb et al., 1998; Le et al., 2000; Shaham et al., 1997). Other brain stress systems implicated in stress-induced reinstatement include norepinephrine, orexin, vasopressin, and nociceptin (see above). Thus, the brain stress systems may impact both the withdrawal/negative affect stage and preoccupation/anticipation stage of the addiction cycle, albeit by engaging different components of the extended amygdala emotional system (central nucleus of the amygdala versus bed nucleus of the stria terminalis; see above), and the dysregulations that comprise the negative emotional state of drug dependence persist during protracted abstinence to set the tone for vulnerability to “craving” by activation of the drug-, cue-, and stress-induced reinstatement neurocircuits now driven by a hypofunctioning, and possibly reorganized, prefrontal system (Volkow and Fowler, 2000).

6.4. Allostasis and Addiction

An overall conceptual framework throughout this review is that drug dependence represents a break with homeostatic brain regulatory mechanisms that regulate the emotional state of the animal. However, the nature of engagement of the brain stress and antistress systems produced by repeated self-administration of drugs of abuse argues that the view of drug addiction representing a simple break with homeostasis is not sufficient to explain a number of key elements of addiction. Drug addiction, similar to other chronic physiological disorders, such as high blood pressure, worsens over time, is subject to significant environmental influences (e.g., external stressors), and leaves a residual neural trace that allows rapid “readdiction” even months and years after detoxification and abstinence. These characteristics of drug addiction have led to a reconsideration of drug addiction as more than simply homeostatic dysregulation of emotional function but rather as a dynamic break with homeostasis of these systems, termed allostasis.

Allostasis is defined as “stability through change” and is different from homeostasis because feed-forward, rather than negative feedback, mechanisms are hypothesized to be engaged (Sterling and Eyer, 1988). However, precisely this ability to mobilize resources quickly and to use feed-forward mechanisms leads to an allostatic state if the systems do not have sufficient time to reestablish homeostasis. An allostatic state can be defined as a state of chronic deviation of the regulatory system from its normal (homeostatic) operating level.

The brain stress systems respond rapidly to anticipated challenges to homeostasis but are slow to habituate or do not readily shut off once engaged (Koob, 1999). Thus, the very physiological mechanism that allows a rapid and sustained response to environmental challenge becomes the engine of pathology if adequate time or resources are not available to shut off the response. Thus, the interaction between CRF and norepinephrine in the brainstem and basal forebrain, the interaction between orexin and CRF in the hypothalamus and basal forebrain, and the interaction between CRF and vasopressin and/or orexin could lead to chronically dysregulated emotional states (Koob, 1999). Similar allostatic mechanisms can be hypothesized to be involved in driving the pathology associated with the brain stress and antistress systems in addiction (Koob and Le Moal, 2001). Repeated challenges (e.g., with drugs of abuse) lead to attempts of the brain via molecular, cellular, and neurocircuitry changes to maintain stability, but at a cost. For the drug addiction framework elaborated here, the residual deviation from normal brain reward threshold regulation is termed an allostatic state. This state represents a combination of chronic elevation of reward set point fueled by numerous neurobiological changes, including decreased function of reward circuits, loss of executive control, and facilitation of stimulus-response associations, but also recruitment of the brain stress systems and compromises to the brain antistress systems. All of these effects contribute to the compulsivity of drug seeking and drug taking known as addiction (Koob and Le Moal, 2008).

Acknowledgments

This work was supported by National Institutes of Health funding from the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute of Diabetes and Digestive and Kidney Diseases, and private funding from the Pearson Center for Alcoholism and Addiction Research. The author would like to thank Michael Arends and Mellany Santos for their help with manuscript preparation, Janet Hightower for her invaluable assistance with the figures, Dr. Charles Neal for his work on the neuroanatomical distribution of nociceptin (Neal et al., 1999) and for his help with Figure 9, and Dr. Michel Le Moal for discussions and the conceptual framework. The author also would like to thank the following people for critical comments and discussions on the manuscript: Dr. Heather Richardson, Dr. Scott Edwards, Dr. Dong Ji, Dr. Kaushik Misra, Dr. Laura Orio, Dr. Nick Gilpin, Dr. Olivier George, Dr. Marisa Roberto, Dr. Sunmee Wee, and Dr. Benjamin Boutrel. This is publication number 19397 from The Scripps Research Institute.

Footnotes

SUPPLEMENTAL DATA

The Supplemental Data can be found with this article online at http://www.neuron.org/cgi/content/full/59/1/11/DC1/.

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Acute Stress Influences Neural Circuits of Reward Processing (2012)

Front Neurosci. 2012; 6: 157.  Published online 2012 November 1. doi:  10.3389/fnins.2012.00157

This article has been cited by other articles in PMC.

Abstract

People often make decisions under aversive conditions such as acute stress. Yet, less is known about the process in which acute stress can influence decision-making. A growing body of research has established that reward-related information associated with the outcomes of decisions exerts a powerful influence over the choices people make and that an extensive network of brain regions, prominently featuring the striatum, is involved in the processing of this reward-related information. Thus, an important step in research on the nature of acute stress’ influence over decision-making is to examine how it may modulate responses to rewards and punishments within reward processing neural circuitry. In the current experiment, we employed a simple reward processing paradigm – where participants received monetary rewards and punishments – known to evoke robust striatal responses. Immediately prior to performing each of two task runs, participants were exposed to acute stress (i.e., cold pressor) or a no stress control procedure in a between-subjects fashion. No stress group participants exhibited a pattern of activity within the dorsal striatum and orbitofrontal cortex (OFC) consistent with past research on outcome processing – specifically, differential responses for monetary rewards over punishments. In contrast, acute stress group participants’ dorsal striatum and OFC demonstrated decreased sensitivity to monetary outcomes and a lack of differential activity. These findings provide insight into how neural circuits may process rewards and punishments associated with simple decisions under acutely stressful conditions.

Keywords: acute stress, cold pressor, reward processing, dorsal striatum, orbitofrontal cortex, fMRI, cortisol

Introduction

Human decision-making often occurs under stressful conditions. The type of stress exposure may be intrinsic or inherent to the decision itself (e.g., choosing between two desirable, but costly options with important consequences) or extrinsic, a pre-existing state which influences decision-making (e.g., stress exposure leading a person to use drugs as a coping mechanism). Thus, understanding how stress exposure influences decision-making is a topic of great interest. Recent efforts suggest that acute stress can modulate risk-taking in decision-making (Preston et al., 2007; Mather et al., 2009; Porcelli and Delgado, 2009), conditioning (for review, see Shors, 2004), and reinforcement learning critical to guiding future decisions (Cavanagh et al., 2010; Petzold et al., 2010). However, less is known about the impact of stress exposure on the processing of affective outcomes, a critical aspect of decision-making. The goal of the current experiment was to examine the influence of exposure to acute stress on reward-related responses in neural circuitry during the delivery of monetary rewards and punishments.

A rich animal literature has delineated a network of regions involved in processing reward-related information, also used to inform decision-making in the human brain (for review, see Schultz, 2006; Balleine et al., 2007; Haber and Knutson, 2010). This reward-related corticostriatal circuitry consists of prefrontal cortex (PFC) regions such as medial PFC and orbitofrontal cortex (OFC) as well as subcortical limbic regions involved in motivation and affect, including the dorsal and ventral striatum. The multifaceted striatum is of particular importance in coding for the subjective value of reward-related information critical to evaluation of outcomes associated with decisions (for review, see O’Doherty et al., 2004; Delgado, 2007; Rangel et al., 2008). Notably, components of the same reward-related neural circuitry have been implicated as a target of the physiological and neurochemical changes associated with engagement of the stress response.

Two complementary biological systems activated by acute stress exposure may influence brain regions involved in reward processing: the sympatho-adrenomedullary axis (i.e., the sympathetic branch of the autonomic nervous system or ANS) and the hypothalamic-pituitary-adrenal axis (HPA; for review, see Ulrich-Lai and Herman, 2009). In response to stress-related homeostatic disruption, the sympathetic ANS quickly responds with the release of catecholamines (CA; e.g., noradrenaline) from the adrenal medulla and ascending CA neurons in communication with the brainstem. As CA release in the peripheral nervous system promotes rapid excitatory changes within the body that enable an organism to deal with the source of the disruption (i.e., the classic “fight-or-flight” response; Cannon, 1915), signals of homeostatic disruption from the brainstem contribute to activation of the HPA via projections to the paraventricular nucleus of the hypothalamus. Proceeding at a slower pace, HPA activation ultimately results in the release of glucocorticoids from the adrenal cortex (i.e., cortisol in humans, corticosterone in rodents; Lupien et al., 2007).

Overall, the influence of acute stress has been studied in the context of memory and other cognitive processes (Joels et al., 2006), but less is known about the impact of stress on processing of reward-related information. One prominent idea is that stress may promote a shift from goal-oriented decision-making toward habit-based decisions that are insensitive to one’s current environment, and can be maladaptive in some contexts (Schwabe and Wolf, 2011; Schwabe et al., 2012). This is supported by studies highlighting changes in structure and function of striatal regions involved in reward-related learning and habit-based decisions (e.g., Delgado, 2007; Tricomi et al., 2009; Balleine and O’Doherty, 2010). For example, rats exposed to chronic stress exhibit marked degradation of dorsomedial striatum and medial PFC with concurrent augmentation of the dorsolateral striatum associated with sustained habitual responses to stimuli even when altered decision outcomes devalue those responses (Dias-Ferreira et al., 2009). In humans, stress-related reductions in reward-related medial PFC responses have been observed in a task involving monetary rewards or neutral outcomes (Ossewaarde et al., 2011), while exposure to acute stress has been linked to reductions in dorsomedial striatal responses to a primary reward (i.e., food; Born et al., 2009).

The current literature suggests that acute stress may modulate neural systems involved in reward processing, particularly the striatum, but a direct test of this hypothesis in humans has not yet been made. The goal of the current study was to utilize a simple reward processing paradigm known to evoke robust striatal responses to examine the influence of exposure to acute stress on outcome evaluation. A potent secondary reinforcer was used: monetary rewards and punishments. A variant of a card guessing task was employed which involved asking participants to make a choice regarding a hidden number on a virtual “card” (Delgado et al., 2000). When participants guessed correctly, they received a monetary reward. When they guessed incorrectly, they received a monetary punishment. Furthermore, rewards and punishments varied in magnitude (high or low). In past research, performance on this task has been shown to evoke robust fMRI blood-oxygen-level-dependent (BOLD) responses in striatal regions. We hypothesized that the previously characterized differential response between rewards and punishments in the striatum would be reduced after exposure to acute stress.

Materials and Methods

Participants

Thirty-four individuals participated in the study. Two participants were excluded from final data analysis, one due to an MRI equipment failure and the other resulting from a request to withdraw from participation. Thus, final data analysis was performed on 32 participants (16 females, 16 males; mean age = 23.41 years, SD years = 4.07). Participants responded to IRB-approved advertisements describing the study. The advertisements also indicated that compensation would be offered for their time at a rate of $25 per hour. All participants gave informed consent according to the guidelines of the Institutional Review Boards of the University of Medicine and Dentistry of New Jersey and Rutgers University.

Procedure

Stress induction

Participants were exposed to acute stress in a between-subjects fashion using a variant on the traditional cold pressor task, which involves immersion of one’s hand into a container of ice-cold water. It is important to note that although water is not inherently incompatible with the MRI environment, if spilled it can be a threat to sensitive MRI equipment (such as the head coil). Additionally, even in the absence of damage due to a spill water can interfere with MRI signal due to its high proton density (Huettel et al., 2008). In the current experiment, we adapted the cold pressor test to fit the MRI environment. To administer cold pressor stress safely once participants were placed within the MRI, rather than prior to entry, an arm wrap was created from a combination of MRI-compatible dry gelpacs and maintained at a temperature of approximately 4°C. This “cold pressor arm wrap” was placed around the right hand and arm of participants assigned to the acute stress group for 2 min immediately prior to each of the two card guessing tasks. For participants assigned to the no stress group, a similar wrap created from towels (at room-temperature) was applied to control for tactile stimulation of the cold pressor arm wrap prior to each card guessing task. Hereafter, when making reference to the two groups collectively the term “experimental groups” will be used.

Card guessing task

In the card guessing task (adapted from Delgado et al., 2000; Delgado et al., 2003) participants were presented with a virtual “card” upon which a question mark was printed for 2 s, representing a number between 1 and 9 (Figure ​(Figure1A).1A). Their task was to make a button press during those 2 s indicating whether they believed the number on the card was higher or lower than the number 5 (choice phase). After making their response during the 2 s choice phase, the actual number appeared on the card for 2 s (outcome phase). If participants had made a correct guess, they received a monetary reward. If their guess was incorrect, they received a monetary punishment. Rewards and punishments could be of high or low magnitude (reward: +$5.00 or +$0.50; punishment: −$2.50 or −$0.25). Importantly, values were manipulated to account for increased sensitivity to monetary losses over gains (i.e., loss aversion), thus ensuring that variations in BOLD signal related to rewards were comparable to those associated with punishments (Tversky and Kahneman, 2004). The magnitude of a reward was concurrently presented during the 2 s outcome phase via presentation of five green check marks (high magnitude) or one green check mark (low magnitude) below the card’s indicated number. Similarly, the magnitude of monetary punishments was represented by five red “×” marks (high magnitude) or one red “×” mark (low magnitude). Participants were explicitly informed as to the monetary value associated with each stimulus prior to beginning the task, but actual dollar amounts were not presented during the task (only the check and × marks). A jittered inter-trial-interval followed the outcome phase during which participants viewed a fixation lasting between 10 and 12 s, followed by the next trial.

Figure 1  
(A) Depiction of the card guessing task. Note, in the example above a correct choice would be “higher than five.” (B) Experimental timeline and cortisol sampling schedule (C = cortisol sample).

Participants engaged in two runs of the card guessing task and were informed that they would receive compensation consistent with their performance (i.e., the outcomes they were presented with) during the card guessing task. Each run involved 40 trials with a total run time of 10 min. Participants were unaware that the outcome of each trial was predetermined such that a balanced presentation of rewards and punishments, as well as high and low magnitudes, was maintained. Thus, of the 40 trials per run 20 were associated with rewards and 20 with punishments, 10 of high/low magnitude for each valence. After completion of the experiment, participants were debriefed as to the actual nature of the task. They then completed a post-experimental questionnaire where they rated subjective stress levels associated with the arm wrap on a seven point Likert scale, as well as how the wrap made them feel (good or bad).

Salivary cortisol measurements

Participants were instructed to avoid eating, drinking (anything other than water), or smoking for 2 h prior to the beginning of the experiment to ensure that saliva samples were untainted. To acquire salivary cortisol data, participants were asked to moisten a Salimetrics Oral Swab (SOS) in their mouths for about 1 min by placing the SOS underneath their tongue. Upon completion of this procedure, the subject withdrew the SOS and the experimenter immediately placed it in an individual centrifuge tube. Three samples were acquired for each participant interspersed throughout the scanning session in approximately 15 min intervals, with the first sample taken after anatomical MRI scans were completed (prior to the first card guessing task). Samples two and three were acquired after each of the two blocks of the card guessing task. Samples were frozen in cold storage at −10°C, packed with dry ice and sent to Salimetrics Laboratory (State College, PA, USA) for duplicate biochemical assay analysis. An experimental timeline and cortisol sampling schedule is presented in Figure ​Figure1B.1B. Importantly, female participants were screened for use of oral contraceptives (OC) that might influence cortisol levels (though this information was not used as an exclusionary criterion per se). Although 5 of the 16 female participants did report use of OC, no significant differences in cortisol levels were observed between OC and non-OC participants as measured by repeated-measures ANOVA. Furthermore, when those five participants were excluded from the imaging analysis the significance and directionality of all reported effects remained unchanged.

fMRI acquisition and analysis

Imaging was performed on a 3T Siemens Allegra scanner equipped with a fast gradient system for echoplanar imaging. A standard radiofrequency head coil with foam padding was used to restrict participants’ head motion while minimizing discomfort. High-resolution axial images (T1-weighted MPRAGE: 256 × 256 matrix, FOV = 256 mm, 176 1 mm axial slices) were obtained from all subjects. Functional images (single-shot gradient echo EPI sequence; TR = 2000 ms; TE = 25 ms; FOV = 192 cm; flip angle = 80°; matrix = 64 × 64; slice thickness = 3 mm) were acquired during performance on the two card guessing task runs. Data were then preprocessed and analyzed using BrainVoyager QX software (version 2.2, Brain Innovation, Maastricht, Netherlands). Preprocessing involved motion correction (six-parameter, three-dimensional), spatial smoothing (4-mm FWHM), voxel-wise linear detrending, high-pass filtering of frequencies (three cycles per time course) and normalization to Talairach stereotaxic space (Talairach and Tournoux, 1988).

General linear models (GLM) were defined at the single-subject level in which predictors were regressed onto the dependent variable of BOLD changes within the brain. Two separate models were generated. In model 1 (outcome valence only), two predictors modeled the outcome phase of the card guessing task based on whether participants had received a rewarding outcome (gain of money) or punishing outcome (loss of money) after their choice. For model 2 (outcome valence and outcome magnitude), the magnitude of rewards and punishments were included, resulting in a model comprised of four predictors: high magnitude reward, low magnitude reward, high magnitude punishment, and low magnitude punishment. In both models, motion parameters generated during fMRI data preprocessing were included as covariates of no-interest (to control for head motion), as was a missed-trial predictor. Two second-level random effects GLMs were then performed.

Based on the random effects GLMs whole-brain statistical parametric maps were generated. Given a priori patterns of BOLD signal defined by a similar contrasts in past work (for review, see Delgado, 2007) it was thought that a Reward – Punishment contrast would best highlight task-related alterations in BOLD signal in regions of the brain known to be involved in processing reward-related information. Using model 1 (outcome valence only) a whole-brain two-tailed contrast was performed on outcome phase BOLD in which rewards and punishments were received (Reward – Punishment), and the difference in BOLD associated with this contrast was contrasted along the between-subjects factor of experimental group (No Stress vs. Acute Stress). Thus, this analysis highlighted brain regions responsive to outcome valence that significantly differed between experimental groups. In a similar whole-brain analysis using model 2, a contrast of high and low magnitude outcomes across outcome valence was performed ([High Reward + High Punishment]  [Low Reward + Low Punishment]) and the difference in BOLD associated with this contrast was computed along the between-subjects factor of experimental group (No Stress vs. Acute Stress). Therefore, this analysis examined brain regions responsive to the magnitude of monetary outcomes that significantly differed between experimental groups.

The resultant contrast maps were then examined to identify statistically significant clusters of activation at a threshold of p < 0.005, with a contiguity threshold of 53 mm voxels. Correction for multiple comparisons was verified through the use of cluster-size thresholding (Forman et al., 1995; Goebel et al., 2006). Thus, only clusters of a sufficient extent so as to be associated with a cluster-level false-positive rate of α = 0.05 remained in the analysis. Additionally, an exploratory analysis of the possible role of participants’ sex was performed in a priori regions of interest given previous sex-related effects observed in the literature (e.g., Lighthall et al., 2011). Specifically, parameter estimates were extracted from significant clusters resultant from both contrasts and examined for potential interactions with sex. Importantly, all post hoc tests within each family of analyses were corrected for multiple comparisons via sequential Bonferroni correction (Holm, 1979).

Results

Reaction time data

A two-tailed independent t-test was performed to examine differences in reaction time in the card guessing task between experimental groups. No significant difference was observed in reaction times for the acute stress (M = 623.31, SEM = 45.91) vs. no stress (M = 633.77, SEM = 43.81) groups, t(30) = 0.17, p > 0.15, d = 0.06.

Subjective stress ratings

Post-experimental subjective ratings of perceived stress experience were examined between acute stress and no stress experimental groups via independent t-tests. These included ratings of how the cold pressor arm wrap made participants feel (good to bad) and how stressful (high to low) the experience was. Compared to the no stress group, the acute stress group rated the arm wrap as feeling significantly worse [t(30) = 4.42, p < 0.001, d = 1.56] and more stressful [t(30) = 3.46, p < 0.01 d = 1.22].

Salivary cortisol data

Salivary cortisol data were excluded for three participants, in one case due to a corruption of the samples and in two cases due to an inability to acquire samples during MRI scanning. Thus, cortisol analyses were conducted on 29 of the 33 participants (13 no stress, 16 acute stress). Mean salivary cortisol levels (in nmol/L) for all three samples by experimental group are reported in Table ​Table1.1. A 3 (Sample 1, 2, or 3) × 2 (Experimental Group: No Stress vs. Stress) repeated-measures ANOVA was performed, but no significant interaction between sample and experimental group was observed, F(2, 54) = 1.77, p = 0.18, η2p= 0.061. Area under the curve with respect to increase (AUCI) was calculated using the trapezoidal method for both experimental groups. This measure is useful in that it represents both time-related changes in salivary cortisol levels as well as the overall intensity of said changes (Pruessner et al., 2003). A one-tailed independent t-test between AUCI for the experimental groups (No stress vs. Acute Stress) indicated a significant increase in cortisol levels for those participants who were exposed to acute stress, t(27) = 1.78, p < 0.05, d = 0.69 (Figure ​(Figure2).2). No significant correlations were observed between cortisol and imaging data presented below.

Table 1  
Mean salivary cortisol levels in nmol/L at baseline, after task run 1, and after task run 2 by experimental group (Mean ± SEM).
Figure 2  
Salivary cortisol area under the curve with respect to increase (AUCI) by experimental group. Note, negative AUCI values (indicating a decrease in salivary cortisol over the course of the experiment) were retained as an “index of decrease” ...

fMRI results

Outcome valence: reward – punishment by experimental group contrast

In the no stress group, multiple brain regions demonstrated greater BOLD signal associated with the reward – punishment contrast than were observed in the acute stress group (see Table ​Table2).2). Prominently featuring among these regions were the dorsal striatum (specifically the right caudate nucleus and left putamen) and the left OFC.

Table 2  
Brain regions that demonstrated differences by experimental group (No Stress vs. Acute Stress) for Reward – Punishment and High – Low Magnitude contrasts (p < 0.005, corrected).

In the right caudate, post hoc paired t-tests suggested that BOLD signal in the no stress group was significantly greater for rewards than punishments, t(15) = 5.69, p < 0.001, d = 0.88 (Figures ​(Figures3A–C).3A–C). No significant difference was observed in the acute stress group, t(15) = 0.74, p > 0.15, d = 0.08. A similar pattern of BOLD signal was observed in the left putamen [no stress, t(15) = 6.57, p < 0.001, d = 0.73; acute stress, t(15) = 1.24, p > 0.15, d = 0.18] and left OFC [no stress, t(15) = 6.80, p < 0.001, d = 1.15; acute stress, t(15) = 0.37, p > 0.15, d = 0.06; see Figure ​Figure4].4]. Thus, whereas the no stress group demonstrated a clear response to rewards over punishments in these regions, the group that had been exposed to acute stress exhibited a lack of responsiveness to reward-related information. All significant t-tests survived sequential Bonferroni correction.

Figure 3  
(A) Right caudate and left putamen clusters exhibiting greater BOLD signal for no stress over acute stress participants. (B) Right caudate nucleus outcome valence × experimental group parameter estimates. (C) Left putamen outcome ...
Figure 4  
(A) Left orbitofrontal cortex cluster exhibiting greater BOLD signal for no stress over acute stress participants. (B) Left orbitofrontal cortex outcome valence × experimental group parameter estimates.

Parameter estimates for these three regions in the acute stress group were then examined in a second analysis for the presence of magnitude-related effects (an orthogonal factor not included in the original contrast) in reward and punishment trials. In the right caudate, post hoc paired t-tests suggested that BOLD signal in the acute stress group was significantly greater for rewards over punishments for outcomes of high magnitude, t(15) = 2.79, p < 0.05, d = 0.31, but not low magnitude, t(15) = −1.37, p > 0.15, d = −0.25. A similar pattern was observed within the left putamen. Acute stress group BOLD differentiated between high magnitude outcomes, t(15) = 2.84, p < 0.05, d = 0.43, but not low magnitude outcomes, t(15) = −0.83, p > 0.15, d = −0.20. Notably, in contrast to the above regions the left OFC in the acute stress group did not significantly differentiate between outcomes of either magnitude [high: t(15) = 1.25, p > 0.15, d = 0.27; low: t(15) = −1.71, p > 0.10, d = −0.34]. All significant t-tests survived sequential Bonferroni correction.

To examine whether or not a difference was present in the stress effect between the two task runs, a region of interest (ROI) analysis was performed investigating right dorsal striatum, left putamen, and left OFC BOLD signal between runs 1 and 2 (using ROIs from the original whole-brain analysis). Parameter estimates extracted from the three aforementioned ROIs were examined via 2 (Run: Run 1 vs. Run 2) × 2 (Outcome Valence: Reward vs. Punishment) × 2 (Experimental Group: No Stress vs. Acute Stress) repeated-measures ANOVA for the purpose of establishing whether or not a difference in BOLD existed as a function of run. No significant interaction was observed between run, experimental group, and outcome valence in the right dorsal striatum, F(1, 30) = 0.001, p > 0.15, η2p= 0.000, left putamen, F(1, 30) = 0.77, p > 0.15, η2p= 0.025, or left OFC, F(1, 30) = 0.31, p > 0.15, η2p= 0.010, suggesting that the previously discussed effects were not different between runs.

Outcome magnitude: high – low by experimental group contrasts

A single brain region was associated with increased BOLD signal for no stress participants in the outcome magnitude contrast: the left inferior frontal gyrus (BA45). Post hoc paired t-tests indicated that no stress participants showed greater BOLD responses to high over low magnitude outcomes (across outcome valence), t(15) = 4.77, p < 0.001, d = 0.76. Acute stress participants, however, demonstrated a trend (which did not survive Bonferroni–Holm correction) toward the reverse pattern – increased BOLD for low over high magnitude outcomes, t(15) = −1.98, p < 0.10, d = −0.38.

Exploratory analyses: sex effects

Salivary cortisol AUCI was examined via univariate ANOVA for sex-related differences in cortisol increases by experimental group. No significant main effect of sex on salivary cortisol was observed, F(1, 25) = 0.52, p = 0.48, η2p= 0.020, nor was a significant sex by experimental group interaction observed, F(1, 25) = 0.03, p = 0.87, η2p= 0.001. Parameter estimates extracted from significant clusters in both contrasts were subjected to a series of 2 (Outcome valence: Reward vs. Punishment) × 2 (Experimental Group: No Stress vs. Acute Stress) × 2 (Sex: male vs. female) repeated-measures ANOVAs to explore -the possible role of sex in stress-related differences in processing of reward-related information. In the right caudate a trend towards a significant experimental group × sex interaction was observed, F(1, 28) = 3.27, p < 0.10, η2p= 0.105. Post hoc independent t-tests indicate that no stress group female participants exhibited greater BOLD signal overall for all outcomes than did males, t(14) = −2.57, p < 0.05, d = −1.28. In contrast acute stress group males’ BOLD was elevated as compared to the no stress group whereas females’ was reduced, resulting in a non-significant difference between the sexes, t(14) = 0.44, p > 0.15, d = 0.22. No other brain regions exhibited trending or significant sex effects.

Discussion

In this study, we sought to investigate how exposure to acute stress influenced neural responses to monetary rewards and punishments. We used a between-subjects approach and tested performance of participants after application of a cold pressor procedure (acute stress group), compared to a control procedure (no stress group) during two runs of a simple card guessing paradigm previously found to yield robust striatal activation to reward responses (e.g., Delgado et al., 2000). Salivary cortisol data and subjective stress ratings confirmed that the stressor (i.e., cold pressor arm wrap adapted for fMRI) was effective. Participants exposed to acute stress exhibited a marked alteration in neural responses to monetary rewards and punishments. Whereas dorsal striatal BOLD signal within the right caudate nucleus and left putamen differentiated between rewarding and punishing outcomes in no stress participants, this was not the case in acute stress participants. A similar pattern of activity was observed in the left OFC. Notably, high magnitude rewards and punishments were resilient to the stress effect in striatal regions but not within OFC. Taken together, these results suggest that exposure to acute stress affects reward-related processing in the dorsal striatum and OFC.

This study complements and augments a growing literature examining the influence of acute stress on human decision-making by attempting to characterize striatal responses to outcome processing under stress. Previous studies have shown modulation of striatal response under stress using different paradigms and reinforcers. For instance, acute stress-related reductions in putamen responses to primary rewards (food images) have been observed (Born et al., 2009), which complements the outcome processing of secondary reinforcers in the current paradigm observed in both caudate and putamen. The consequences of decreased sensitivity to reward processing is a question for future research, but it is informed by a recent study suggesting that increased life stress and reduced ventral striatum reactivity to rewards (i.e., positive performance feedback) interact to predict low levels of positive affect on a depression scale (Nikolova et al., 2012). This converges with previous behavioral work indicating a reduction in responsiveness to rewards under acute stress (Bogdan and Pizzagalli, 2006) which the current study builds upon with the observation of reductions in reward-related responses in the dorsal striatum after acute stress exposure.

An interesting observation from our study is that the stress modulation effect was observed in the dorsal, but not the ventral, striatum. A null finding, however, should not be interpreted as a lack of stress modulation of ventral striatum responses (in fact, stress-related ventral striatal activation has been observed in a non-reward-related task; Pruessner et al., 2008); rather, it highlights the sensitivity of dorsal striatum activity to stress modulation (e.g., Sinha et al., 2005). The dorsal striatum, particularly the caudate, has often been found to be robustly recruited by the reward paradigm used in the current paper (for review, see Delgado, 2007). Further, the dorsal striatum has been posited to function as an “actor” that maintains information about action-contingent response-reward associations to guide future decisions based on the outcomes of past ones, while the ventral portion a “critic” that predicts possible future rewards (O’Doherty et al., 2004; Tricomi et al., 2004). Thus, by impairing the ability of the dorsal striatum to distinguish between rewarding vs. punishing outcomes, acute stress may interfere with the use of information provided by past decisions to guide future choices.

Within the dorsal striatum itself, a functional subdivision suggests that the medial portion of the dorsal striatum is involved in flexible, goal-oriented, and action-contingent decision-making whereas the lateral portion mediates habitual and stimulus bound decisions (Balleine et al., 2007; Tricomi et al., 2009). In the current experiment, it is plausible that stress-related changes in BOLD signal observed in the dorsomedial striatum (i.e., caudate) and dorsolateral striatum (i.e., putamen) mark the beginning of a shift from goal-directed to habitual processing of decision outcomes, although further work is necessary to test this hypothesis using an affective learning paradigm. The hypothesis is consistent with previous behavioral work in support of stress’ ability to shift decision-related processing from goal-oriented to habitual (i.e., as in instrumental conditioning; Schwabe and Wolf, 2011). Importantly, decreased sensitivity to reward processing in the dorsal striatum may have important clinical applications with respect to decision-making and one’s general affect. For instance, stress- and drug-cue associated alterations in dorsal striatal function have been implicated in relapse in drug/alcohol addiction (Sinha and Li, 2007) and reduced dorsal striatal responses to rewards have been observed in unmedicated individuals suffering from major depressive disorder (Pizzagalli et al., 2009).

Another brain region implicated in processing of reward-related information is the OFC, which in this experiment also exhibited alterations in responsiveness to rewards and punishments. It has been suggested that this region may be involved in outcome evaluation by coding for the subjective value of said decision outcomes (O’Doherty et al., 2001a). For example, increases in OFC BOLD have been observed during delivery of pleasant as compared to aversive gustatory stimuli (O’Doherty et al., 2001b). Although stress-related reductions in brain function during reward processing have been somewhat studied in neighboring prefrontal regions such as the medial PFC (Ossewaarde et al., 2011) OFC has received less attention in this regard, making it an ideal topic for future research. This is especially the case with respect to the effects of stress on drug addiction, as this region may play a role in the inability of addicts to alter their behavior based on likely outcomes or consequences – leading to relapse (Schoenbaum and Shaham, 2008). A notable exception is a recent study suggesting the necessity of concurrent CA and glucocorticoid activation in reductions in OFC sensitivity to reward-related information (e.g., Schwabe et al., 2012).

With respect to the mechanism underlying the findings of the current study, several plausible interpretations can be considered. It has been established that glucocorticoid responses to cold pressor stress are less extreme than have been observed in other stress induction techniques, such as stressors involving a psychosocial component (e.g., McRae et al., 2006; Schwabe et al., 2008). In the current study, this is reflected by mild-to-moderate acute stress group increases in cortisol. In contrast, it is likely that sympathetic ANS activation remains comparable between cold pressor and other forms of stress. Another consideration is that in the current study initial acute stress exposure occurred immediately prior to the first card guessing task, followed 15 min later by a second stress exposure and card guessing task. As the effects of glucocorticoid release in this type of paradigm would likely be genomic (i.e., slow and long-lasting; Sapolsky et al., 2000) it is possible that they did not influence brain function in the first task run. Yet, the observed decrease in striatal and OFC responsiveness to reward-related information was present in both task runs. Further, as stress-related increases in cortisol were modest here it is possible that glucocorticoids did not contribute to the effect at all. Thus, lack of data that can speak to the dynamics of sympathetic ANS activation (e.g., skin conductance or salivary alpha amylase; Rohleder et al., 2004) constitutes a study limitation. While the paradigm employed here was not designed to address these issues, it is likely that contextual factors including the nature and timing of stress exposure and the mode of reward-related information involved in the task play an important role.

Some studies suggest that sex differences may play a role in stress-related alterations in striatal reward processing. For example, studies examining the influence of acute stress on risk-tasking have established fluctuations in dorsal striatal function as a function of gender (Lighthall et al., 2009, 2011). There participants performed the Balloon Analog Risk Task, which involves making a button press to expand a virtual balloon for monetary rewards. With each button press, more money is gained – but at a certain point the balloon will explode. Thus, participants risk losing all winnings if they continue to expand the balloon to gain additional rewards. It was observed that under acute stress males take more risks and exhibit increases in dorsal striatal function, whereas females show the reverse pattern, as compared to no stress participants. In the current study, a trend toward a sex difference along similar lines was also observed in the dorsal striatum – though to a lesser degree. No stress females’ BOLD for outcomes was elevated above males’. While BOLD signals to outcomes did decrease for acutely stressed females and increased for males, the result was more extreme in the Lighthall et al. (2009, 2011) studies. This may relate to the fact that risk-taking tasks such as the balloon task involve anticipation of potential outcomes in addition to an outcome evaluation component, while also requiring participants make complex choices balancing potential rewards against potential punishments. It may be the case that the simple outcome evaluation paradigm used in our study is less sensitive to sex differences than more dynamic and complex risk-taking paradigms.

In sum, this paper used a novel approach to induce stress in the fMRI scanner (the cold pressor arm wrap) and observed that exposure to acute stress modulated reward-related circuitry. Specifically, participants under stress showed decreased differential responses to reward and punishment in the dorsal striatum and OFC. Future studies may try to probe if this decreased differential response is driven by a diminished response to rewards (as previously observed in the literature, e.g., Born et al., 2009) or an increase in sensitivity to negative outcomes. Further, additional research is needed to clarify how neural responses to these distinct reinforcers might influence subsequent decision-making under stress.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

This research was supported by funding from the National Institute on Drug Abuse to Mauricio R. Delgado (R01DA027764).

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Addiction is a Reward Deficit and Stress Surfeit Disorder (2013)

Front Psychiatry. 2013; 4: 72.

This article has been cited by other articles in PMC.

Abstract

Drug addiction can be defined by a three-stage cycle – binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation – that involves allostatic changes in the brain reward and stress systems. Two primary sources of reinforcement, positive and negative reinforcement, have been hypothesized to play a role in this allostatic process. The negative emotional state that drives negative reinforcement is hypothesized to derive from dysregulation of key neurochemical elements involved in the brain reward and stress systems. Specific neurochemical elements in these structures include not only decreases in reward system function (within-system opponent processes) but also recruitment of the brain stress systems mediated by corticotropin-releasing factor (CRF) and dynorphin-κ opioid systems in the ventral striatum, extended amygdala, and frontal cortex (both between-system opponent processes).

CRF antagonists block anxiety-like responses associated with withdrawal, block increases in reward thresholds produced by withdrawal from drugs of abuse, and block compulsive-like drug taking during extended access.

Excessive drug taking also engages the activation of CRF in the medial prefrontal cortex, paralleled by deficits in executive function that may facilitate the transition to compulsive-like responding.

Neuropeptide Y, a powerful anti-stress neurotransmitter, has a profile of action on compulsive-like responding for ethanol similar to a CRF1 antagonist. Blockade of the κ opioid system can also block dysphoric-like effects associated with withdrawal from drugs of abuse and block the development of compulsive-like responding during extended access to drugs of abuse, suggesting another powerful brain stress system that contributes to compulsive drug seeking. The loss of reward function and recruitment of brain systems provide a powerful neurochemical basis that drives the compulsivity of addiction.

Keywords: opponent process, extended amygdala, corticotropin-releasing factor, dynorphin, reward, compulsive, withdrawal, prefrontal cortex

What is Addiction?

Addiction can be defined as a chronic, relapsing disorder that has been characterized by (i) a compulsion to seek and take drugs, (ii) loss of control over drug intake, and (iii) emergence of a negative emotional state (e.g., dysphoria, anxiety, and irritability) that defines a motivational withdrawal syndrome when access to the drug is prevented (1). The occasional, limited, recreational use of a drug is clinically distinct from escalated drug use, the loss of control over drug intake, and the emergence of compulsive drug-seeking behavior that characterize addiction.

Addiction has been conceptualized as a three-stage cycle – binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation that worsens over time and involves allostatic changes in the brain reward and stress systems. Two primary sources of reinforcement, positive and negative reinforcement, have been hypothesized to play a role in this allostatic process. Positive reinforcement is defined as the process by which presentation of a stimulus increases the probability of a response; negative reinforcement is defined as the process by which removal of an aversive stimulus (or negative emotional state of withdrawal in the case of addiction) increases the probability of a response. Reward is operationally defined similarly to positive reinforcement as any stimulus that increases the probability of a response but also has a positive hedonic effect. Different theoretical perspectives from experimental psychology (positive and negative reinforcement frameworks), social psychology (self-regulation failure framework), and neurobiology (counteradaptation and sensitization frameworks) can be superimposed on the stages of the addiction cycle (1). These stages are thought to feed into each other, become more intense, and ultimately lead to the pathological state known as addiction (Figure ​(Figure1).1). The neural substrates for the two sources of reinforcement that play a key role in the allostatic neuroadaptations derive from two key motivational systems required for survival: the brain reward and brain stress systems.

Figure 1    
Theoretical framework relating addiction cycle to motivation for drug seeking. The figure shows the change in the relative contribution of positive and negative reinforcement constructs during the development of substance dependence [taken with permission ...

Brain Reward Systems

Comprehension of a brain reward system was greatly facilitated by the discovery of electrical brain stimulation reward by Olds and Milner (2). Brain stimulation reward involves widespread neurocircuitry throughout the brain, but the most sensitive sites include the trajectory of the medial forebrain bundle that connects the ventral tegmental area with the basal forebrain [(2–,4); Figure ​Figure2].2]. All drugs of abuse acutely decrease brain stimulation reward thresholds [i.e., increase or facilitate reward; (5)]. When drugs are administered chronically, withdrawal from drugs of abuse increases reward thresholds (decrease reward). Although much emphasis was initially placed on the role of ascending monoamine systems, particularly the dopamine system, in the medial forebrain bundle in mediating brain stimulation reward, other non-dopaminergic systems in the medial forebrain bundle clearly play a key role (6–,8). Indeed, the role of dopamine is hypothesized to be more indirect. Many studies suggest that activation of the mesolimbic dopamine system attaches incentive salience to stimuli in the environment (9–,11) to drive the performance of goal-directed behavior (12) or activation in general (13, 14), and work concerning the acute reinforcing effects of drugs of abuse supports this hypothesis.

Figure 2    
Neurotransmitter pathways and receptor systems implicated in the acute reinforcing effects of drugs of abuse within the medial forebrain bundle. A sagittal rodent brain section is shown. The medial forebrain bundle represents ascending and descending ...

Our knowledge of the neurochemical substrates that mediate the acute reinforcing effects of drugs of abuse has contributed significantly to our knowledge of the brain reward system. These substrates include connections of the medial forebrain bundle reward system with primary contributions from the ventral tegmental area, nucleus accumbens, and amygdala. Much evidence supports the hypothesis that psychostimulant drugs dramatically activate the mesolimbic dopamine system (projections from the ventral tegmental area to the nucleus accumbens) during limited-access drug self-administration and that this mechanism is critical for mediating the rewarding effects of cocaine, amphetamines, and nicotine. However, evidence supports both dopamine-dependent and dopamine-independent neural substrates for opioid and alcohol reward (15–,17). Serotonin systems, particularly those involving serotonin 5-HT1B receptor activation in the nucleus accumbens, have also been implicated in the acute reinforcing effects of psychostimulant drugs, whereas μ-opioid receptors in both the nucleus accumbens and ventral tegmental area mediate the reinforcing effects of opioids. Opioid peptides in the ventral striatum and amygdala have been hypothesized to mediate the acute reinforcing effects of ethanol self-administration, largely based on the effects of opioid antagonists. Inhibitory γ-aminobutyric acid (GABA) systems are activated both pre- and postsynaptically in the amygdala by ethanol at intoxicating doses, and GABA receptor antagonists block ethanol self-administration [for comprehensive reviews, see (16, 17)].

For the binge/intoxication stage of the addiction cycle, studies of the acute reinforcing effects of drugs of abuse per se have identified key neurobiological substrates. Evidence is strong for a role for dopamine in the acute reinforcing actions of psychostimulants, opioid peptide receptors in the acute reinforcing effects of opioids, and GABA and opioid peptides in the acute reinforcing actions of alcohol. Important anatomical circuits include the mesocorticolimbic dopamine system that originates in the ventral tegmental area and local opioid peptide systems, both of which converge on the nucleus accumbens (17).

Brain Stress Systems

The brain stress systems can be defined as neurochemical systems that are activated during exposure to acute stressors or in a chronic state of stress and mediate species-typical behavioral responses. These behavioral responses in animals range from freezing to flight and typically have face and predictive validity for similar behavior responses in humans. For example, animals exposed to a stressor will show an enhanced freezing response to a conditioned fear stimulus, an enhanced startle response to a startle stimulus, avoidance of open areas, open arms, or height, and enhanced species-typical responses to an aversive stimulus (e.g., burying a shock probe in the defensive burying test). Key neuronal/neurochemical systems with circumscribed neurocircuitry that mediate behavioral responses to stressors include glucocorticoids, corticotropin-releasing factor (CRF), norepinephrine, and dynorphin, and key neurochemical systems that act in opposition to the brain stress systems include neuropeptide Y (NPY), nociceptin, and endocannabinoids [for reviews, see (18–,20)]. For the purposes of this review, two brain stress systems with prominent roles in driving the dark side of addiction will be considered: CRF and dynorphin.

Corticotropin-releasing factor

Corticotropin-releasing factor is a 41-amino-acid polypeptide that controls hormonal, sympathetic, and behavioral responses to stressors (21, 22). Central administration of CRF mimics the behavioral response to activation and stress in rodents, and administration of competitive CRF receptor antagonists generally has anti-stress effects [for reviews, see (23–,26)]. Two major CRF receptors have been identified, with CRF1 receptor activation associated with increased stress responsiveness (27) and CRF2 receptor activation associated with decreases in feeding and decreases in stress responsiveness (28, 29), although there is some controversy in this area (30). CRF neurons are present in the neocortex, the extended amygdala, the medial septum, the hypothalamus, the thalamus, the cerebellum, and autonomic midbrain and hindbrain nuclei (31). Extensive research has been performed on CRF neurons in the paraventricular nucleus of the hypothalamus (PVN), central nucleus of the amygdala (CeA), and bed nucleus of the stria terminalis (BNST), demonstrating a key role for PVN CRF neurons in controlling the pituitary adrenal response to stress (32) and a key role for BNST and CeA CRF in mediating the negative affective responses to stress and drug withdrawal (33).

The neuroanatomical entity termed the extended amygdala (34) may represent a common anatomical substrate that integrates brain arousal-stress systems with hedonic processing systems to produce the neuroadaptations associated with the development of addiction (see below). The extended amygdala is composed of the CeA, BNST, and a transition zone in the medial (shell) subregion of the nucleus accumbens. Each of these regions has cytoarchitectural and circuitry similarities (34). The extended amygdala receives numerous afferents from limbic structures, such as the basolateral amygdala and hippocampus, and sends efferents to the medial part of the ventral pallidum and a large projection to the lateral hypothalamus, thus further defining the specific brain areas that interface classical limbic (emotional) structures with the extrapyramidal motor system (35). CRF in the extended amygdala has long been hypothesized to play a key role not only in fear conditioning (36, 37) but also in the emotional component of pain processing (38).

Dynorphin-κ opioid system

Dynorphins are opioid peptides that derive from the prodynorphin precursor and contain the leucine (leu)-enkephalin sequence at the N-terminal portion of the molecule and are the presumed endogenous ligands for the κ opioid receptor (39). Dynorphins are widely distributed in the central nervous system (40) and play a role in neuroendocrine regulation, pain regulation, motor activity, cardiovascular function, respiration, temperature regulation, feeding behavior, and stress responsivity (41). Dynorphins bind to all three opioid receptors but show a preference for κ receptors (39). Dynorphin-κ receptor system activation produces some actions that are similar to other opioids (analgesia) but others opposite to those of μ opioid receptors in the motivational domain. Dynorphins produce aversive dysphoric-like effects in animals and humans and have been hypothesized to mediate negative emotional states (42–,45).

Dopamine receptor activation in the nucleus accumbens shell stimulates a cascade of events that ultimately lead to cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation and subsequent alterations in gene expression, notably the activation of the expression of prodynorphin mRNA. Subsequent activation of dynorphin systems has been hypothesized to feed back to decrease dopamine release in the mesolimbic dopamine system (46–,50) and glutamate release in the nucleus accumbens (51, 52). Both of these changes may contribute to the dysphoric syndrome associated with cocaine dependence. In vivo microdialysis studies have also provided evidence that κ opioid receptors located in the prefrontal cortex (PFC) and ventral tegmental area also regulate the basal activity of mesocortical dopamine neurons (53, 54). In the extended amygdala, enhanced dynorphin action may also activate brain stress responses, such as CRF (55), or CRF in turn may activate dynorphin (56, 57).

Dynamic Changes in Reward: Opponent Process

Changes in reinforcement were inextricably linked with hedonic, affective, or emotional states in addiction in the context of temporal dynamics by Solomon’s opponent-process theory of motivation. Solomon and Corbit (58) postulated that hedonic, affective, or emotional states, once initiated, are automatically modulated by the central nervous system through mechanisms that reduce the intensity of hedonic feelings. The a-process includes affective or hedonic habituation (or tolerance), and the b-process includes affective or hedonic withdrawal (abstinence). The a-process in drug use consists of positive hedonic responses, occurs shortly after the presentation of a stimulus, correlates closely with the intensity, quality, and duration of the reinforcer, and shows tolerance. In contrast, the b-process in drug use appears after the a-process has terminated, consists of negative hedonic responses, and is sluggish in onset, slow to build up to an asymptote, slow to decay, and gets larger with repeated exposure. The thesis we have elaborated is that there is a neurocircuitry change in specific neurochemical systems that account for the b-process. Such opponent processes are hypothesized to begin early in drug taking, reflecting not only deficits in brain reward system function but also the recruitment of brain stress systems. Furthermore, we hypothesize that the recruitment of brain stress systems forms one of the major sources of negative reinforcement in addiction. Finally, we have hypothesized that such changes result not in a return to homeostasis of reward/stress function but in allostasis of reward/stress function that continues to drive the addiction process (Figure ​(Figure33).

Figure 3    
(A) The standard pattern of affective dynamics produced by (left) a relatively novel unconditioned stimulus (i.e., in a non-dependent state) and (right) a familiar, frequently repeated unconditioned stimulus (i.e., in a dependent state) [taken with permission ...

Allostasis, originally conceptualized to explain persistent morbidity of arousal and autonomic function, can be defined as “stability through change.” Allostasis involves a feed-forward mechanism rather than the negative feedback mechanisms of homeostasis, with continuous reevaluation of need and continuous readjustment of all parameters toward new set points. An allostatic state has been defined as a state of chronic deviation of the regulatory system from its normal (homeostatic) operating level (15). Allostatic load was defined as the “long-term cost of allostasis that accumulates over time and reflects the accumulation of damage that can lead to pathological states” (59).

Opponent process-like negative emotional states have been characterized in humans by acute and protracted abstinence from all major drugs of abuse (60–,62). Similar results have been observed in animal models with all major drugs of abuse using intracranial self-stimulation (ICSS) as a measure of hedonic tone. Withdrawal from chronic cocaine (63), amphetamine (64), opioids (65), cannabinoids (66), nicotine (67), and ethanol (68) leads to increases in reward threshold during acute abstinence, and some of these elevations in threshold can last for up to 1 week (69). These observations lend credence to the hypothesis that opponent processes in the hedonic domain have an identifiable neurobiological basis and provide an impetus for defining the mechanisms involved. Understanding the mechanisms that drive this increase in reward thresholds is key to understanding the mechanisms that drive negative reinforcement in addiction.

Such elevations in reward threshold begin rapidly and can be observed within a single session of self-administration (70), bearing a striking resemblance to human subjective reports of acute withdrawal. Dysphoria-like responses also accompany acute opioid and ethanol withdrawal (71, 72). Here, naloxone administration following single injections of morphine increased reward thresholds, measured by ICSS, and increased thresholds with repeated morphine and naloxone-induced withdrawal experience (71). Similar results were observed during repeated acute withdrawal from ethanol (72).

Neuroadaptations Responsible for Opponent Process

One hypothesis is that drug addiction progresses from a source of positive reinforcement that may indeed involve a form of sensitization of incentive salience, as argued by Robinson and Berridge (9), to sensitization of opponent processes that set up a powerful negative reinforcement process. A further elaboration of this hypothesis is that there are both within- and between-system neuroadaptations to excessive activation of the reward system at the neurocircuitry level. Within-system neuroadaptations are defined as the process by which the primary cellular response element to the drug (circuit A) itself adapts to neutralize the drug’s effects. Persistence of the opposing effects after the drug disappears produces adaptation. A between-system neuroadaptation is a circuitry change, in which B circuits (i.e., the stress or anti-reward circuits) are activated by circuit A (i.e., the reward circuit). In the present treatise, within-system neuroadaptations can dynamically interact with a between-system neuroadaptation, in which circuit B (i.e., the anti-reward circuit) is activated either in parallel or in series to suppress the activity of circuit A (see below).

Animal models of the transition to an addiction-like state as defined by escalation in drug self-administration with prolonged access

A progressive increase in the frequency and intensity of drug use is one of the major behavioral phenomena that characterize the development of addiction and has face validity with the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV): “The substance is often taken in larger amounts and over a longer period than was intended” (American Psychological Association, 1994). A framework with which to model the transition from drug use to drug addiction can be found in recent animal models of prolonged access to intravenous cocaine self-administration. Historically, animal models of cocaine self-administration involved the establishment of stable behavior from day to day to allow the reliable interpretation of data provided by within-subject designs aimed at exploring the neuropharmacological and neurobiological bases of the reinforcing effects of acute cocaine. Up until 1998, after the acquisition of self-administration, rats were typically allowed access to cocaine for 3 h or less per day to establish highly stable levels of intake and patterns of responding between daily sessions. This was a useful paradigm for exploring the neurobiological substrates for the acute reinforcing effects of drugs of abuse.

However, in an effort to explore the possibility that differential access to drugs of abuse may have more face validity for the compulsive-like responding observed in addiction, animals have been allowed extended access to all major drugs of abuse (Figure ​(Figure4).4). Increased intake was observed in the extended-access group for intravenous cocaine, methamphetamine, heroin, and nicotine and oral alcohol during extended access and dependence (73–,79). For example, when animals were allowed access for 1 and 6 h to different doses of cocaine, after escalation, both the long-access (LgA) and short-access (ShA) animals titrated their cocaine intake, but LgA rats consistently self-administered almost twice as much cocaine at any dose tested, further suggesting an upward shift in the set point for cocaine reward in the escalated animals (80–,82).

Figure 4    
(A) Effect of drug availability on cocaine intake (mean ± SEM). In long-access (LgA) rats (n = 12) but not short-access (ShA) rats (n = 12), the mean total cocaine intake started to increase significantly ...

Consistent with the hypothesis that extended access to drugs of abuse produces compulsive-like responding, in which animals will “continue to respond in the face of adverse consequences” (another DSM-IV criteria for Substance Dependence), animals with extended access that show escalation in self-administration also show increased responding on a progressive-ratio schedule of reinforcement [(83–,85); Figure ​Figure5].5]. Changes in the reinforcing and incentive effects of drug intake that are consistent with the increases in progressive-ratio responding have been observed following extended access and include increased drug-induced reinstatement after extinction, a decreased latency to goal time in a runway model for drug reward, and responding in the face of punishment (86–,92). Altogether, these results suggest that drug taking with extended-access changes the motivation to seek the drug. Some have argued that enhanced drug taking reflects a sensitization of reward (93), but studies of locomotor sensitization suggest that locomotor sensitization occurs independently of escalation (94–,96). The increased brain reward thresholds and neuropharmacological studies outlined below argue for a reward deficit state that drives the increased drug taking during extended access.

Figure 5    
(A) Dose-response function of cocaine by rats responding under a progressive-ratio schedule. Test sessions under a progressive-ratio schedule ended when rats did not achieve reinforcement within 1 h. The data are expressed as the number of injections ...

Animals escalate their intake of drugs with extended access, with a parallel increase in reward thresholds

The hypothesis that compulsive cocaine use is accompanied by a chronic perturbation in brain reward homeostasis has been tested in animal models of escalation in drug intake with prolonged access combined with measures of brain stimulation reward thresholds. Animals implanted with intravenous catheters and allowed differential access to intravenous self-administration of cocaine showed increases in cocaine self-administration from day to day in the LgA group (6 h; LgA) but not in the ShA group (1 h; ShA). The differential exposure to cocaine self-administration had dramatic effects on reward thresholds that progressively increased in LgA rats but not ShA or control rats across successive self-administration sessions (97). Elevations in baseline reward thresholds temporally preceded and were highly correlated with escalation in cocaine intake (Figure ​(Figure6).6). Post-session elevations in reward thresholds failed to return to baseline levels before the onset of each subsequent self-administration session, thereby deviating more and more from control levels. The progressive elevation in reward thresholds was associated with a dramatic escalation in cocaine consumption that was observed previously (97). Similar results have been observed with extended access to methamphetamine (98) and heroin (99). Rats allowed 6 h access to methamphetamine or 23 h access to heroin also showed a time-dependent increase in reward thresholds that paralleled the increases in heroin intake (Figure ​(Figure6).6). Similar results of parallel increases in brain reward thresholds with escalation of nicotine intake have been observed with extended access to nicotine (100).

Figure 6    
(A) Relationship between elevation in ICSS reward thresholds and cocaine intake escalation (Left). Percent change from baseline response latencies (3 h and 17–22 h after each self-administration session; first data point indicates ...

Brain Reward System Substrates for the Negative Reinforcement Associated with Addiction (Within-System Neuroadaptations)

The withdrawal/negative affect stage can be defined as the presence of motivational signs of withdrawal in humans, including chronic irritability, physical pain, emotional pain [i.e., hyperkatifeia; (101)], malaise, dysphoria, alexithymia, and loss of motivation for natural rewards. It is characterized in animals by increases in reward thresholds during withdrawal from all major drugs of abuse. More compelling, as noted above, in animal models of the transition to addiction, similar changes in brain reward thresholds occur that temporally precede and are highly correlated with escalation in drug intake (97–,99). Such acute withdrawal is associated with decreased activity of the mesocorticolimbic dopamine system, reflected by electrophysiological recordings and in vivo microdialysis [(102–,104); Figure ​Figure77].

Figure 7    
(A) The left panel shows the effect of ethanol withdrawal on absolute extracellular dopamine concentrations in the nucleus accumbens in ethanol-withdrawn rats. The middle and right panels show the spontaneous activity of antidromically identified ventral ...

Human imaging studies of individuals with addiction during withdrawal or protracted abstinence have generated results that are consistent with animal studies. There are decreases in dopamine D2 receptors (hypothesized to reflect hypodopaminergic functioning), hyporesponsiveness to dopamine challenge (105), and hypoactivity of the orbitofrontal-infralimbic cortex system (105). These are hypothesized to be within-system neuroadaptations that may reflect presynaptic release or postsynaptic receptor plasticity.

In the context of chronic alcohol administration, multiple molecular mechanisms have been hypothesized to counteract the acute effects of ethanol that could be considered within-system neuroadaptations. For example, chronic ethanol decreases γ-aminobutyric acid (GABA) receptor function, possibly through downregulation of the α1 subunit (106, 107). Chronic ethanol also decreases the acute inhibition of adenosine reuptake [i.e., tolerance develops to the inhibition of adenosine by ethanol; (108)]. Perhaps more relevant to the present treatise, whereas acute ethanol activates adenylate cyclase, withdrawal from chronic ethanol decreases CREB phosphorylation in the amygdala and is linked to decreases in the function of NPY and anxiety-like responses observed during acute ethanol withdrawal (109, 110).

Brain Stress System Substrates for the Negative Reinforcement Associated with Addiction (Between-System Neuroadaptations)

Brain neurochemical systems involved in arousal-stress modulation have been hypothesized to be engaged within the neurocircuitry of the brain stress systems in an attempt to overcome the chronic presence of the perturbing drug and restore normal function despite the presence of drug (18). Both the hypothalamic-pituitary-adrenal (HPA) axis and extrahypothalamic brain stress system mediated by CRF are dysregulated by chronic administration of all major drugs with dependence or abuse potential, with a common response of elevated adrenocorticotropic hormone, corticosterone, and amygdala CRF during acute withdrawal (24, 69, 111–,116). Indeed, activation of the HPA response may be an early dysregulation associated with excessive drug taking that ultimately “sensitizes” the extrahypothalamic CRF systems (33, 92).

As noted above, the excessive release of dopamine and opioid peptides produces subsequent activation of dynorphin systems, which has been hypothesized to feed back to decrease dopamine release and also contribute to the dysphoric syndrome associated with cocaine dependence (48). Dynorphins produce aversive dysphoric-like effects in animals and humans and have been hypothesized to mediate negative emotional states (42–,45).

A common response to acute withdrawal and protracted abstinence from all major drugs of abuse is the manifestation of anxiety-like responses that are reversed by CRF antagonists. Withdrawal from repeated administration of cocaine produces an anxiogenic-like response in the elevated plus maze and defensive burying test, both of which are reversed by administration of CRF receptor antagonists (117, 118). Opioid dependence also produces irritability-like effects that are reversed by CRF receptor antagonists (119, 120). Ethanol withdrawal produces anxiety-like behavior that is reversed by intracerebroventricular administration of CRF1/CRF2 peptidergic antagonists (121) and small-molecule CRF1 antagonists (122–,124) and intracerebral administration of a peptidergic CRF1/CRF2 antagonist into the amygdala (125). Thus, some effects of CRF antagonists have been localized to the CeA (125). Precipitated withdrawal from nicotine produces anxiety-like responses that are also reversed by CRF antagonists (77, 126). CRF antagonists injected intracerebroventricularly or systemically also block the potentiated anxiety-like responses to stressors observed during protracted abstinence from chronic ethanol (127–,131).

Another measure of negative emotional states during drug withdrawal in animals is conditioned place aversion, in which animals avoid an environment previously paired with an aversive state. Such place aversions, when used to measure the aversive stimulus effects of withdrawal, have been observed largely in the context of opioids (132, 133). Systemic administration of a CRF1 receptor antagonist and direct intracerebral administration of a peptide CRF1/CRF2 antagonist also decreased opioid withdrawal-induced place aversions (134–,136). These effects have been hypothesized to be mediated by actions in the extended amygdala. The selective CRF1 antagonist antalarmin blocked the place aversion produced by naloxone in morphine-dependent rats (134), and a CRF peptide antagonist injected into the CeA also reversed the place aversion produced by methylnaloxonium injected into the CeA (135). CRF1 knockout mice failed to show conditioned place aversion to opioid withdrawal and failed to show an opioid-induced increase in dynorphin mRNA in the nucleus accumbens (136).

A compelling test of the hypothesis that CRF-induced increases in anxiety-like responses during drug withdrawal has motivational significance in contributing to negative emotional states is the observation that CRF antagonists can reverse the elevation in reward thresholds produced by drug withdrawal. Nicotine and alcohol withdrawal-induced elevations in reward thresholds were reversed by a CRF antagonist (137, 138). These effects have been localized to both the CeA and nucleus accumbens shell (139).

Enhanced dynorphin action is hypothesized to mediate the depression-like, aversive responses to stress, and dysphoric-like responses during withdrawal from drugs of abuse (49, 56, 57, 140–,145). For example, pretreatment with a κ-opioid receptor antagonist blocked stress-induced analgesia and stress-induced immobility (57), decreased anxiety-like behavior in the elevated plus maze and open field, decreased conditioned fear in fear-potentiated startle (145), and blocked depressive-like behavior induced by cocaine withdrawal (140).

Brain Stress Substrates that Mediate Drug Taking with Extended Access

Corticotropin-releasing factor, compulsive-like drug seeking, and the extended amygdala

The ability of CRF antagonists to block the anxiogenic-like and aversive-like motivational effects of drug withdrawal predicted motivational effects of CRF antagonists in animal models of extended access to drugs. CRF antagonists selectively blocked the increased self-administration of drugs associated with extended access to intravenous self-administration of cocaine (146), nicotine (77), and heroin [(147); Figure ​Figure8].8]. For example, systemic administration of a CRF1 antagonist blocked the increased self-administration of nicotine associated with withdrawal in extended-access (23 h) animals (77).

Figure 8    
Effects of CRF1 antagonist on compulsive-like responding for drugs of abuse in rats with extended access to drug (A). The effect of the CRF1 receptor antagonist MPZP on operant self-administration of alcohol in dependent and non-dependent rats. Testing ...

Corticotropin-releasing factor antagonists also blocked the increased self-administration of ethanol in dependent rats [(124); Figure ​Figure8].8]. For example, exposure to repeated cycles of chronic ethanol vapor produced substantial increases in ethanol intake in rats during both acute withdrawal and protracted abstinence [2 weeks post-acute withdrawal; (76, 148)]. Intracerebroventricular administration of a CRF1/CRF2 antagonist blocked the dependence-induced increase in ethanol self-administration during both acute withdrawal and protracted abstinence (149). Systemic injections of small-molecule CRF1 antagonists also blocked the increased ethanol intake associated with acute withdrawal (124) and protracted abstinence (150). When administered directly into the CeA, a CRF1/CRF2 antagonist blocked ethanol self-administration in ethanol-dependent rats (151). These effects appear to be mediated by the actions of CRF on GABAergic interneurons within the CeA, and a CRF antagonist administered chronically during the development of dependence blocked the development of compulsive-like responding for ethanol (116). Altogether, these results suggest that CRF in the basal forebrain may also play an important role in the development of the aversive motivational effects that drive the increased drug-seeking associated with cocaine, heroin, nicotine, and alcohol dependence.

Dynorphin, compulsive-like drug seeking, and the extended amygdala

Recent evidence suggests that the dynorphin-κ opioid system also mediates compulsive-like drug responding (methamphetamine, heroin, and alcohol) with extended access and dependence. Evidence from our laboratory has shown a small-molecule κ antagonist selectively blocked responding on a progressive-ratio schedule for cocaine in rats with extended access (152). Even more compelling is that excessive drug self-administration can also be blocked by κ antagonists (152–,155) and may be mediated by the shell of the nucleus accumbens (156). However, the neurobiological circuits involved in mediating the effects of activation of the dynorphin-κ opioid system on the escalation of methamphetamine intake with extended access, remain unknown.

NPY, compulsive drug seeking, and the extended amgydala

Neuropeptide Y is a neuropeptide with dramatic anxiolytic-like properties localized to multiple brain regions but heavily innervating the amygdala. It is hypothesized to have effects opposite to CRF in the negative motivational state of withdrawal from drugs of abuse and as such increases in NPY function may act in opposition to the actions of increases in CRF (157). Significant evidence suggests that activation of NPY in the CeA can block the motivational aspects of dependence associated with chronic ethanol administration. NPY administered intracerebroventricularly blocked the increased drug intake associated with ethanol dependence (158, 159). NPY also decreased excessive alcohol intake in alcohol-preferring rats (160). Injection of NPY directly into the CeA (161) and viral vector-enhanced expression of NPY in the CeA also blocked the increased drug intake associated with ethanol dependence (162). At the cellular level, NPY, like CRF1 antagonists, blocks the increase in GABA release in the CeA produced by ethanol and also when administered chronically blocks the transition to excessive drinking with the development of dependence (163). The role of NPY in the actions of other drugs of abuse is limited, particularly with regard to dependence and compulsive drug seeking. NPY5 receptor knockout mice have a blunted response to the rewarding effects of cocaine (164, 165), and NPY knockout mice show hypersensitivity to cocaine self-administration (166). NPY itself injected intracerebroventricularly facilitated heroin and cocaine self-administration and induced reinstatement of heroin seeking in limited-access rats (167, 168). An NPY Y2 antagonist, possibly acting presynaptically to release NPY, blocked social anxiety associated with nicotine withdrawal (169), and NPY injected intracerebroventricularly blocked the somatic signs but not reward deficits associated with nicotine withdrawal (170). However, the role of NPY in compulsive drug seeking with extended-access remains to be studied. The hypothesis here would be that NPY is a buffer or homeostatic response to between-system neuroadaptations that can return the brain emotional systems to homeostasis (157, 171).

Corticotropin-releasing factor, stress, and the frontal cortex

Converging lines of evidence suggest that impairment of medial PFC (mPFC) cognitive function and overactivation of the CeA may be linked to the development of compulsive-like responding for drugs of abuse during extended access (172–,174). Extended access to cocaine self-administration induced an escalated pattern of cocaine intake associated with an impairment of working memory and decrease in the density of dorsomedial PFC (dmPFC) neurons that lasted for months after cocaine cessation (172). Whereas LgA and ShA rats exhibited a high percentage of correct responses in the delayed non-matching-to-sample task under low cognitive demand (delay < 10 s), increasing the working memory load (i.e., close to the capacity limit of working memory) by increasing the delay from 10 to 70 and 130 s revealed a robust working memory deficit in LgA rats. Furthermore, the magnitude of escalation of cocaine intake was negatively correlated with working memory performance in ShA and LgA rats with the 70- and 130-s delays but not with the 10-s delay or with baseline performance during training, demonstrating that the relationship between the escalation of cocaine intake and behavioral performance in this task was restricted to working memory performance under high cognitive demand. The density of neurons and oligodendrocytes in the dmPFC was positively correlated with working memory performance. A lower density of neurons or oligodendrocytes in the dmPFC was associated with more severe working memory impairment. Working memory was also correlated with the density of oligodendrocytes in the orbitofrontal cortex (OFC), suggesting that OFC alterations after escalated drug intake may play a role in working memory deficits. However, no correlation was found between working memory performance and neuronal density in the OFC, suggesting that OFC neurons may be less vulnerable to the deleterious effects of chronic cocaine exposure than dmPFC neurons. Thus, PFC dysfunction may exacerbate the loss of control associated with compulsive drug use and facilitate the progression to drug addiction.

Similar results have been observed in an animal model of binge alcohol consumption, even before the development of dependence. Using an animal model of escalation of alcohol intake with chronic intermittent access to alcohol, in which rats are given continuous (24 h per day, 7 days per week) or intermittent (3 days per week) access to alcohol (20% v/v) using a two-bottle choice paradigm, FBJ murine osteosarcoma viral oncogene homolog (Fos) expression in the mPFC, CeA, hippocampus, and nucleus accumbens were measured and correlated with working memory and anxiety-like behavior (175). Abstinence from alcohol in rats with a history of escalation of alcohol intake specifically recruited GABA and CRF neurons in the mPFC and produced working memory impairments associated with excessive alcohol drinking during acute (24–72 h) but not protracted (16–68 days) abstinence. The abstinence from alcohol was associated with a functional disconnection of the mPFC and CeA but not mPFC or nucleus accumbens. These results show that recruitment of a subset of GABA and CRF neurons in the mPFC during withdrawal and disconnection of the PFC CeA pathway may be critical for impaired executive control over motivated behavior, suggesting that dysregulation of mPFC interneurons may be an early index of neuroadaptation in alcohol dependence.

Brain Stress Systems in Addiction: An Allostatic View

More importantly for the present thesis, as dependence and withdrawal develop, brain anti-reward systems, such as CRF and dynorphin, are recruited in the extended amygdala. We hypothesize that this brain stress neurotransmitter that is known to be activated during the development of excessive drug taking comprises a between-system opponent process, and this activation is manifest when the drug in removed, producing anxiety, hyperkatifeia, and irritability symptoms associated with acute and protracted abstinence. Notably, however, there is evidence of CRF immunoreactivity in the ventral tegmental area, and a CRF1 receptor antagonist injected directly into the ventral tegmental area blocked the social stress-induced escalation of cocaine self-administration (176). Altogether, these observations suggest between-system/within-system neuroadaptations that were originally hypothesized for dynorphin by Carlezon and Nestler (177), in which activation of CREB by excessive dopamine and opioid peptide receptor activation in the nucleus accumbens triggers the induction of dynorphin to feed back to suppress dopamine release. Thus, we hypothesize that anti-reward circuits are recruited as between-system neuroadaptations (178) during the development of addiction and produce aversive or stress-like states (179–,181) via two mechanisms: direct activation of stress-like, fear-like states in the extended amygdala (CRF) and indirect activation of a depression-like state by suppressing dopamine (dynorphin).

A critical problem in drug addiction is chronic relapse, in which addicted individuals return to compulsive drug taking long after acute withdrawal. This corresponds to the preoccupation/anticipation stage of the addiction cycle outlined above. Koob and Le Moal also hypothesized that the dysregulations that comprise the “dark side” of drug addiction persist during protracted abstinence to set the tone for vulnerability to “craving” by activating drug-, cue-, and stress-induced reinstatement neurocircuits that are now driven by a reorganized and possibly hypofunctioning prefrontal system. The hypothesized allostatic, dysregulated reward, and sensitized stress state produces the motivational symptoms of acute withdrawal and protracted abstinence and provides the basis by which drug priming, drug cues, and acute stressors acquire even more power to elicit drug-seeking behavior (92). Thus, the combination of decreases in reward system function and recruitment of anti-reward systems provides a powerful source of negative reinforcement that contributes to compulsive drug-seeking behavior and addiction. A compelling argument can be made that the neuroplasticity that charges the CRF stress system may indeed begin much earlier that previously thought via stress actions in the PFC.

The overall conceptual theme argued here is that drug addiction represents an excessive and prolonged engagement of homeostatic brain regulatory mechanisms that regulate the response of the body to rewards and stressors. The dysregulation of the incentive salience systems may begin with the first administration of drug (182), and the dysregulation of the stress axis may begin with the binge and subsequent acute withdrawal, triggering a cascade of changes, from activation of the HPA axis to activation of CRF in the PFC to activation of CRF in the extended amygdala to activation of dynorphin in the ventral striatum (Figure ​(Figure9).9). This cascade of overactivation of the stress axis represents more than simply a transient homeostatic dysregulation; it also represents the dynamic homeostatic dysregulation termed allostasis.

Figure 9    
Diagram of the hypothetical “within-system” and “between-system” changes that lead to the “darkness within.” (Top) Circuitry for drug reward with major contributions from mesolimbic dopamine and opioid peptides ...

Repeated challenges, such as with drugs of abuse, lead to attempts of the brain stress systems at the molecular, cellular, and neurocircuitry levels to maintain stability but at a cost. For the drug addiction framework elaborated here, the residual decrease in the brain reward systems and activation of the brain stress systems to produce the consequent negative emotional state is termed an allostatic state (15). This state represents a combination of recruitment of anti-reward systems and consequent chronic decreased function of reward circuits, both of which lead to the compulsive drug seeking and loss of control over intake. How these systems are modulated by other known brain emotional systems localized to the basal forebrain, where the ventral striatum and extended amygdala project to convey emotional valence, how frontal cortex dysregulations in the cognitive domain are linked to impairments in executive function to contribute to the dysregulation of the extended amygdala, and how individuals differ at the molecular-genetic level of analysis to convey loading on these circuits remain challenges for future research.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

The author would like to thank Michael Arends and Mellany Santos for their assistance with the preparation of this manuscript. Research was supported by National Institutes of Health grants AA006420, AA020608, AA012602, and AA008459 from the National Institute on Alcohol Abuse and Alcoholism, DA010072, DA004043, DA023597, and DA004398 from the National Institute on Drug Abuse, and DK26741 from the National Institute of Diabetes and Digestive and Kidney Diseases. Research also was supported by the Pearson Center for Alcoholism and Addiction Research. This is publication number 24002 from The Scripps Research Institute.

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Brain stress systems in the amygdala and addiction (2009)

Brain Res. 2009 October 13; 1293: 61–75. Pu10.1016/j.brainres.2009.03.038

Abstract

Dysregulation of the brain emotional systems that mediate arousal and stress is a key component of the pathophysiology of drug addiction. Drug addiction is a chronically relapsing disorder characterized by a compulsion to seek and take drugs and the development of dependence and manifestation of a negative emotional state when the drug is removed. Activation of brain stress systems is hypothesized to be a key element of the negative emotional state produced by dependence that drives drug-seeking through negative reinforcement mechanisms. The focus of the present review is on the role of two key brain arousal/stress systems in the development of dependence. Emphasis is placed on the neuropharmacological actions of corticotropin-releasing factor (CRF) and norepinephrine in extrahypothalamic systems in the extended amygdala, including the central nucleus of the amygdala, bed nucleus of the stria terminalis, and a transition area in the shell of the nucleus accumbens. Compelling evidence argues that these brain stress systems, a heretofore largely neglected component of dependence and addiction, play a key role in engaging the transition to dependence and maintaining dependence once it is initiated. Understanding the role of the brain stress and anti-stress systems in addiction not only provides insight into the neurobiology of the “dark side” of addiction but also provides insight into the organization and function of basic brain emotional circuitry that guides motivated behavior.

Keywords: Addiction, Neurobiology, Stress, Corticotropin-releasing factor, Norepinephrine, Extended amygdala

1. Conceptual framework: addiction, stress, motivational withdrawal, and negative reinforcement

Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take the drug and loss of control in limiting intake. A third key element included by some and particularly relevant to the present review is the emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) when access to the drug is prevented (defined here as dependence) (Koob and Le Moal, 1997, 2008). Addiction is used interchangeably in the present treatise with the term Substance Dependence (currently defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition; American Psychiatric Association, 1994), but “dependence” with a lower-case “d” will be used to define the manifestation of a withdrawal syndrome when chronic drug administration is stopped (Koob and Le Moal, 2006). The occasional but limited use of a drug with the potential for abuse or dependence is distinct from the emergence of a chronic drug-dependent state.

Stress can be defined as responses to demands (usually noxious) upon the body (Selye, 1936) that historically have been defined by various physiological changes that include activation of the hypothalamic-pituitary-adrenal (HPA) axis. This activation is characterized by the release of adrenal steroids triggered by the release of adrenocorticotropic hormone (ACTH) from the pituitary. Adrenocorticotropic hormone release is controlled, in turn, by the liberation of hypothalamic corticotropin-releasing factor (CRF) into the pituitary portal system of the median eminence. A definition of stress more compatible with its many manifestations in the organism is any alteration in psychological homeostatic processes (Burchfield, 1979). The construct of stress subsequently has been linked to the construct of arousal and as such may represent the extreme pathological continuum of overactivation of the body's normal activational or emotional systems (Hennessy and Levine, 1979; Pfaff, 2006).

Drug addiction has been conceptualized as a disorder that involves elements of both impulsivity and compulsivity (Fig. 1). Impulsivity can be defined as an individual engaging in rapid, unplanned reactions to internal and external stimuli without regard for the negative consequences of these reactions to the individual or others. Compulsivity can be defined as perseveration in responding in the face of adverse consequences or perseveration in the face of incorrect responses in choice situations. Both of these elements reflect increased motivation to seek drug and have face validity with the symptoms of Substance Dependence as outlined by the American Psychiatric Association.

Fig. 1
Schematic for the progression of alcohol dependence over time, illustrating the shift in underlying motivational mechanisms. From initial, positively reinforcing, pleasurable drug effects, the addictive process progresses over time to being maintained ...

Collapsing the cycles of impulsivity and compulsivity yields a composite addiction cycle comprising three stages–preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect–in which impulsivity often dominates at the early stages and compulsivity dominates at terminal stages. As an individual moves from impulsivity to compulsivity, a shift occurs from positive reinforcement driving the motivated behavior to negative reinforcement driving the motivated behavior (Koob, 2004). Negative reinforcement can be defined as the process by which removal of an aversive stimulus (e.g., negative emotional state of drug withdrawal) increases the probability of a response (e.g., dependence-induced drug intake). These three stages are conceptualized as interacting with each other, becoming more intense, and ultimately leading to the pathological state known as addiction (Koob and Le Moal, 1997).

The thesis of this review is that a key element of the addiction process involves a profound activation of stress systems in the brain that interacts but is independent of hormonal stress systems. Such brain stress systems are further hypothesized to be localized to the circuitry of the central nucleus of the amygdala and to produce the negative emotional state that becomes the powerful motivation for drug-seeking associated with compulsive use. The focus of this paper will be on the role of CRF and norepinephrine in addiction as a central element of a complex system that maintains emotional homeostasis.

2. Hormonal stress systems: hypothalamic-pituitary-adrenal axis

The HPA axis is composed of three major structures: the paraventricular nucleus of the hypothalamus, the anterior lobe of the pituitary gland, and the adrenal gland (for review, see Smith and Vale, 2006). Neurosecretory neurons in the medial parvocellular subdivision of the paraventricular nucleus synthesize and release CRF into the portal blood vessels that enter the anterior pituitary gland. Binding of CRF to the CRF1 receptor on pituitary corticotropes induces the release of ACTH into the systemic circulation. Adrenocorticotropic hormone in turn stimulates glucocorticoid synthesis and secretion from the adrenal cortex. The HPA axis is finely tuned via negative feedback from circulating glucocorticoids that act on glucocorticoid receptors in two main brain areas: the paraventricular nucleus and the hippocampus. The hypophysiotropic neurons of the paraventricular nucleus of the hypothalamus are innervated by numerous afferent projections, including from brainstem, other hypothalamic nuclei, and forebrain limbic structures.

3. Brain stress systems: corticotropin-releasing factor and norepinephrine

Corticotropin-releasing factor is a 41 amino acid polypeptide that controls hormonal, sympathetic, and behavioral responses to stressors. The discovery of other peptides with structural homology, notably the urocortin family (urocortins 1, 2, and 3), suggested broad neurotransmitter roles for the CRF systems in behavioral and autonomic responses to stress (Bale and Vale, 2004; Hauger et al., 2003). Substantial CRF-like immunoreactivity is present in the neocortex, extended amygdala, medial septum, hypothalamus, thalamus, cerebellum, and autonomic midbrain and hindbrain nuclei (Charlton et al., 1987; Swanson et al., 1983). The distribution of urocortin 1 projections overlaps with CRF but also has a different distribution, including visual, somatosensory, auditory, vestibular, motor, tegmental, parabrachial, pontine, median raphe, and cerebellar nuclei (Zorrilla and Koob, 2005). The CRF1 receptor has abundant, widespread expression in the brain that overlaps significantly with the distribution of CRF and urocortin 1.

The endogenous selective CRF2 agonists–the type 2 urocortins urocortin 2 (Reyes et al., 2001) and urocortin 3 (Lewis et al., 2001)–differ from urocortin 1 and CRF in their neuropharmacological profiles. Urocortins 2 and 3 show high functional selectivity for the CRF2 receptor and have neuroanatomical distributions that are distinct from those of CRF and urocortin 1. Urocortins 2 and 3 are notably salient in hypothalamic nuclei that express the CRF2 receptor, including the supraoptic nucleus, magnocellular neurons of the paraventricular nucleus, and forebrain, including the ventromedial hypothalamus, lateral septum, bed nucleus of the stria terminalis, and medial and cortical amygdala (Li et al., 2002). The CRF2(a) receptor isoform is localized neuronally in brain areas distinct from those of the CRF/urocortin 1/CRF1 receptor system, such as the ventromedial hypothalamic nucleus, paraventricular nucleus of the hypothalamus, supraoptic nucleus, nucleus tractus solitarius, area postrema, lateral septum, and bed nucleus of the stria terminalis.

Norepinephrine binds to three distinct families of receptors, α1, α2, and β-adrenergic, each of which has three receptor subtypes (Rohrer and Kobilka, 1998). The α1 receptor family comprises α1a, α1b, and α1d. Each subtype activates phospholipase C and is coupled to the inositol phosphate second messenger system via the G-protein Gq. A centrally active α1 receptor antagonist used in drug dependence research is prazosin. The α2 family comprises α2a, α2b, and α2c. Each subtype inhibits adenylate cyclase via coupling to the inhibitory G-protein Gi. Two α2 drugs commonly used in drug dependence research are the α2 agonist clonidine and the α2 antagonist yohimbine. The β-adrenergic receptor family comprises β1, β2, and β3. Each subtype activates adenylate cyclase via coupling to the G-protein Gs. Few β-adrenergic drugs have been explored in drug dependence research, with the exception of the β-adrenergic antagonist propranolol, presumably because of poor brain bioavailability.

Perhaps more intriguing is the pronounced interaction of central nervous system CRF systems and central nervous system norepinephrine systems. Conceptualized as a feed-forward system at multiple levels of the pons and basal forebrain, CRF activates norepinephrine, and norepinephrine in turn activates CRF (Koob, 1999). Much pharmacologic, physiologic, and anatomic evidence supports an important role for a CRF-norepinephrine interaction in the region of the locus coeruleus in response to stressors (Valentino et al., 1991, 1993; Van Bockstaele et al., 1998). However, norepinephrine also stimulates CRF release in the paraventricular nucleus of the hypothalamus (Alonso et al., 1986), bed nucleus of the stria terminalis, and central nucleus of the amygdala. Such feed-forward systems were hypothesized to have powerful functional significance for mobilization of an organism for environmental challenge, but such a mechanism may be particularly vulnerable to pathology (Koob, 1999).

4. Extended amygdala: interface of stress and addiction

Recent neuroanatomical data and new functional observations have provided support for the hypothesis that the neuroanatomical substrates for many of the motivational effects of drug addiction may involve a common neural circuitry that forms a separate entity within the basal forebrain, termed the “extended amygdala” (Alheid and Heimer, 1988). The extended amygdala represents a macro-structure composed of several basal forebrain structures: the bed nucleus of the stria terminalis, central medial amygdala, and a transition zone in the posterior part of the medial nucleus accumbens (i.e., posterior shell) (Johnston, 1923; Heimer and Alheid, 1991). These structures have similarities in morphology, immunohistochemistry, and connectivity (Alheid and Heimer, 1988), and they receive afferent connections from limbic cortices, the hippocampus, basolateral amygdala, midbrain, and lateral hypothalamus. The efferent connections from this complex include the posterior medial (sublenticular) ventral pallidum, ventral tegmental area, various brainstem projections, and perhaps most intriguing from a functional point of view, a considerable projection to the lateral hypothalamus (Heimer and Alheid, 1991). Key elements of the extended amygdala include not only neurotransmitters associated with the positive reinforcing effects of drugs of abuse, but also major components of the brain stress systems associated with the negative reinforcement of dependence (Koob and Le Moal, 2005).

5. Pharmacological evidence for a role of CRF and norepinephrine in negative emotional states associated with drug withdrawal

A common response to acute withdrawal and protracted abstinence from all major drugs of abuse is the manifestation of anxiety-like or aversive-like responses. Animal models have revealed anxiety-like responses to all major drugs of abuse during acute withdrawal (Fig. 2). The dependent variable is often a passive response to a novel and/or aversive stimulus, such as the open field or elevated plus maze, or an active response to an aversive stimulus, such as defensive burying of an electrified metal probe. Withdrawal from repeated administration of cocaine produces an anxiogenic-like response in the elevated plus maze and defensive burying test, both of which are reversed by administration of CRF antagonists (Sarnyai et al., 1995; Basso et al., 1999). Precipitated withdrawal in opioid dependence also produces anxiety-like effects (Schulteis et al., 1998; Harris and Aston-Jones, 1993). Precipitated withdrawal from opioids also produces place aversions (Stinus et al., 1990). Here, in contrast to conditioned place preference, rats exposed to a particular environment while undergoing precipitated withdrawal to opioids spend less time in the withdrawal-paired environment when subsequently presented with a choice between that environment and an unpaired environment. Systemic administration of a CRF1 receptor antagonist and direct intracerebral administration of a peptide CRF1/CRF2 antagonist also decreased opioid withdrawal-induced place aversions (Stinus et al., 2005; Heinrichs et al., 1995). Functional noradrenergic antagonists (i.e., β1 antagonist and α2 agonist) blocked opioid withdrawal-induced place aversion (Delfs et al., 2000).

Fig. 2
Effects of a CRF antagonist on ethanol, nicotine, cocaine, and opioid motivational withdrawal. (A) Effect of intracerebroventricular administration of the CRF peptide antagonist α-helical CRF9–41 in rats tested in the elevated plus maze ...

Ethanol withdrawal produces anxiety-like behavior that is reversed by intracerebroventricular administration of CRF1/CRF2 peptidergic antagonists (Baldwin et al., 1991), intracerebral administration of a peptidergic CRF1/CRF2 antagonist into the amygdala (Rassnick et al., 1993), and systemic injections of small molecule CRF1 antagonists (Knapp et al., 2004; Overstreet et al., 2004; Funk et al., 2007). CRF antagonists injected intracerebroventricularly or systemically also blocked the potentiated anxiety-like responses to stressors observed during protracted abstinence from chronic ethanol (Breese et al., 2005; Valdez et al., 2003). Precipitated withdrawal from nicotine produces anxiety-like responses that are also reversed by CRF antagonists (Tucci et al., 2003; George et al., 2007). These effects of CRF antagonists have been localized to the central nucleus of the amygdala (Rassnick et al., 1993).

6. Neurochemical evidence for a role of CRF and norepinephrine in motivational effects of acute drug withdrawal

Chronic administration of drugs of abuse either via self-administration or passive administration increases extracellular CRF from the extended amygdala measured by in vivo microdialysis (Fig. 3). Continuous access to intravenous self-administration of cocaine for 12 h increased extracellular CRF in dialysates of the central nucleus of the amygdala (Richter and Weiss, 1999). Opioid withdrawal induced after chronic morphine pellet implantation in rats increased extracellular CRF in the central nucleus of the amygdala (Weiss et al., 2001). Acute nicotine administration and withdrawal from chronic nicotine elevated CRF extrahypothalamically in the basal forebrain (Matta et al., 1997). Increased CRF-like immunoreactivity has been observed in adult rats exposed to nicotine during adolescence and has been linked to an anxiety-like phenotype (Slawecki et al., 2005). Extracellular CRF has been shown to be increased in the central nucleus of the amygdala during precipitated withdrawal from chronic nicotine administered via minipump (George et al., 2007). During ethanol withdrawal, extrahypothalamic CRF systems become hyperactive, with an increase in extracellular CRF within the central nucleus of the amygdala and bed nucleus of the stria terminalis of dependent rats during acute withdrawal (2–12 h) (Funk et al., 2006; Merlo-Pich et al., 1995; Olive et al., 2002). Precipitated withdrawal from chronic cannabinoid exposure also increased CRF in the central nucleus of the amygdala (Rodriguez de Fonseca et al., 1997). Altogether these results show that all major drugs of abuse produce a dramatic increase in extracellular levels of CRF measured by in vivo microdialysis during acute withdrawal after chronic drug administration.

Fig. 3
(A) Effects of ethanol withdrawal on CRF-like immunoreactivity (CRF-L-IR) in the rat amygdala determined by microdialysis. Dialysate was collected over four 2 h periods regularly alternated with nonsampling 2 h periods. The four sampling periods corresponded ...

Norepinephrine has long been hypothesized to be activated during withdrawal from drugs of abuse. Opioids decreased firing of noradrenergic neurons in the locus coeruleus, and the locus coeruleus was activated during opioid withdrawal (Nestler et al., 1994). The chronic opioid effects on the locus coeruleus noradrenergic system have been shown in an extensive series of studies to involve upregulation of the cyclic adenosine monophosphate (cAMP) signaling pathway and increased expression of tyrosine hydroxylase (Nestler et al., 1994). Recent studies suggest that neurotrophic factors (e.g., brain-derived neurotrophic factor and neurotrophin-3 originating from non-noradrenergic neurons) may be essential for opiate-induced molecular neuroadaptations in the locus coeruleus noradrenergic pathway (Akbarian et al., 2001, 2002). Substantial evidence also suggests that in animals and humans, central noradrenergic systems are activated during acute withdrawal from ethanol and may have motivational significance. Alcohol withdrawal in humans is associated with activation of noradrenergic function in cerebrospinal fluid (Borg et al., 1981, 1985; Fujimoto et al., 1983). Chronic nicotine self-administration (23 h access) increased norepinephrine release in the paraventricular nucleus of the hypothalamus (Sharp and Matta, 1993; Fu et al., 2001) and the amygdala (Fu et al., 2003). However, during the late maintenance phase of 23 h access to nicotine, norepinephrine levels were no longer elevated in the amygdala, suggesting some desensitization/tolerance-like effect (Fu et al., 2003).

7. Pharmacological evidence of a role for CRF and norepinephrine in increased motivation for drug-seeking in withdrawal

The ability of neuropharmacological agents to block the anxiogenic-like and aversive-like motivational effects of drug withdrawal would predict motivational effects of these agents in animal models of extended access to drugs. Animal models of extended access involve exposure of the animals to extended sessions of intravenous self-administration of drugs (cocaine, 6 h; heroin, 12 h; nicotine, 23 h) and passive vapor exposure (14 h on/12 h off) for ethanol. Animals are then tested for self-administration at various times into withdrawal, ranging from 2–6 h for ethanol to days with nicotine. CRF antagonists selectively blocked the increased self-administration of drugs associated with extended access to intravenous self-administration of cocaine (Specio et al., 2008), nicotine (George et al., 2007), and heroin (Greenwell et al., 2009a). CRF antagonists also blocked the increased self-administration of ethanol in dependent rats (Funk et al., 2007) (Table 1, Fig. 4).

Table 1
Role of CRF in dependence
Fig. 4
Effects of small molecule CRF1 receptor antagonists on drug self-administration in dependent rats (A) Effect of small molecule CRF1 receptor antagonist MPZP on operant self-administration of alcohol (g/kg) in dependent and nondependent rats. Testing was ...

Evidence for specific sites in the brain mediating these CRF antagonistic actions have centered on the central nucleus of the amygdala. Injections of CRF antagonists injected directly into the central nucleus of the amygdala blocked the aversive effects of precipitated opioid withdrawal (Heinrichs et al., 1995) and blocked the anxiogenic-like effects of ethanol withdrawal (Rassnick et al., 1993). Intracerebroventricular administration of the CRF1/CRF2 antagonist D-Phe CRF12–41 blocked the dependence-induced increase in ethanol self-administration during both acute withdrawal and protracted abstinence (Valdez et al., 2004; Rimondini et al., 2002). When administered directly into the central nucleus of the amygdala, lower doses of D-Phe CRF12–41 blocked ethanol self-administration in ethanol-dependent rats (Funk et al., 2006). A CRF2 agonist, urocortin 3, injected into the central nucleus of the amygdala also blocked ethanol self-administration in ethanol-dependent rats (Funk et al., 2007), suggesting a reciprocal CRF1/CRF2 action in the central nucleus of the amygdala contributing to the mediation of withdrawal-induced drinking in the rat (Bale and Vale, 2004).

These data suggest an important role for CRF, primarily within the central nucleus of the amygdala, in mediating the increased self-administration associated with dependence and suggest that CRF in the basal forebrain also may have an important role in the development of the aversive motivational effects that drive the increased drug-seeking associated with cocaine, heroin, and nicotine dependence.

Support also exists for a role of norepinephrine systems in ethanol self-administration and in the increased self-administration associated with dependence. Significant evidence supports an interaction between central nervous system norepinephrine and ethanol reinforcement and dependence. In a series of early studies, Amit and colleagues showed that voluntary ethanol consumption was decreased by both selective pharmacological and neurotoxin-specific disruption of noradrenergic function (Amit et al., 1977; Brown and Amit, 1977). Administration of selective dopamine β-hydroxylase inhibitors produced a marked suppression of alcohol intake in previously alcohol-preferring rats (Amit et al., 1977). Central administration of the neurotoxin 6-hydroxydopamine at doses that massively depleted norepinephrine neurons also blocked ethanol consumption in rats (Brown and Amit, 1977; Mason et al., 1979). Intragastric self-administration of ethanol also was blocked by dopamine β-hydroxylase inhibition (Davis et al., 1979). Selective depletion of norepinephrine in the medial prefrontal cortex of high ethanol-consuming C57BL/6J mice decreased ethanol consumption (Ventura et al., 2006). Mice with knockout of brain norepinephrine via knockout of the dopamine β-hydroxylase gene have a reduced preference for ethanol (Weinshenker et al., 2000).

In more recent studies, the α1 noradrenergic receptor antagonist prazosin blocked the increased drug intake associated with ethanol dependence (Walker et al., 2008), extended access to cocaine (Wee et al., 2008), and extended access to opioids (Greenwell et al., 2009b) (Table 2, Fig. 5). Thus, converging data suggest that disruption of noradrenergic function blocks ethanol reinforcement, that noradrenergic neurotransmission is enhanced during drug withdrawal, and that noradrenergic functional antagonists can block the increased drug self-administration associated with acute withdrawal.

Table 2
Role of norepinephrine in dependence
Fig. 5
Effects of the α1 adrenergic receptor antagonist prazosin on drug self-administration in dependent rats. (A) Mean (± SEM) responses for ethanol during 30 min sessions in nondependent and ethanol-dependent animals following 0.0 and 1.5 ...

8. Cellular basis in the central nucleus of the amygdala for motivational effects of CRF and norepinephrine interactions in dependence

Cellular studies using electrophysiological techniques have shown that γ-aminobutyric acid (GABA) activity within interneurons of the extended amygdala may reflect the negative emotional state of motivational significance for drug-seeking in dependence (Koob, 2008). CRF itself enhances GABAA inhibitory postsynaptic potentials (IPSCs) in whole-cell recordings of the central nucleus of the amygdala and bed nucleus of the stria terminalis in brain slice preparations, and this effect is blocked by CRF1 antagonists and is blocked in CRF1 knockout mice (Nie et al., 2004; Kash and Winder, 2006). In the amygdala, CRF is localized within a subpopulation of GABAergic neurons in the bed nucleus of the stria terminalis and central nucleus of the amygdala different from those that colocalize enkephalin (Day et al., 1999).

For norepinephrine, evidence suggests a similar mechanism in the bed nucleus of the stria terminalis in which whole-cell recordings from slice preparations demonstrated that norepinephrine enhanced GABAergic neurotransmission. The noradrenergic effect appeared to be via the α1 receptor (Dumont and Williams, 2004). If the data from the central nucleus of the amygdala and the bed nucleus of the stria terminalis are combined, then certain consistencies are evident: CRF and norepinephrine increase GABAergic activity, actions at the cellular level that are parallel to the behavioral effects described above with neuropharmacological studies.

Because GABAergic drugs are typically robust anxiolytics, the fact that anxiogenic-like neurotransmitters would activate GABAergic neurotransmission and anxiolytic-like neurotransmitters would depress GABAergic transmission in a brain region known to be involved in stress-related behavior may seem paradoxical. However, local GABAergic activity within the central nucleus of the amygdala may functionally influence neuronal responsivity of inhibitory central nucleus of the amygdala gating that regulates information flow through local intra-amygdaloidal circuits (i.e., by disinhibition of the central nucleus of the amygdala), leading to increased inhibition in downstream regions that mediate the behavioral response (Fig. 6).

Fig. 6
Neurocircuitry in the central nucleus of the amygdala relating CRF and norepinephrine in motivational withdrawal. CRF is hypothesized not only to drive GABAergic interneurons that engage hypothalamic and midbrain emotional systems, but also to directly ...

Changes in neurotransmission in the brain stress systems with the development of dependence may reflect GABAergic neuron sensitization to the actions of the brain stress/anti-stress systems. The augmented GABA release produced by ethanol in the central nucleus of the amygdala increased even further in dependent animals, demonstrated both by electrophysiological and in vivo microdialysis measures (Roberto et al., 2004). The ethanol-induced enhancement of GABAergic IPSCs was blocked by CRF1 antagonists (Nie et al., 2004; Roberto et al., 2004) and was not observed in CRF1 knockout mice (Nie et al., 2004). Thus, chronic ethanol-induced changes in neuronal activity of GABA interneurons in the central nucleus of the amygdala can be linked at the cellular level to actions of CRF that reflect behavioral results in animal models of excessive drinking.

Given that most neurons in the central nucleus of the amygdala are GABAergic (Sun and Cassell, 1993), the mechanism mediating downstream targets associated with emotional states may reflect either inhibitory neurons with recurrent or feed-forward connections or inhibitory projection neurons to brainstem or downstream regions (e.g., bed nucleus of the stria terminalis). Thus, the central nucleus of the amygdala may be hypothesized to be a “gate” that regulates the flow of information through intra-amygdaloidal circuits. Moreover, the fine-tuning of the GABAergic inhibitory system in the central nucleus of the amygdala may be a prerequisite for controlling both local and output neurons to downstream nuclei (Fig. 6).

9. Brain stress systems and addiction

Drug addiction, similar to other chronic physiological and psychological disorders such as high blood pressure, worsens over time, is subject to significant environmental influences (e.g., external stressors), and leaves a residual neural trace that allows rapid “re-addiction” even months and years after detoxification and abstinence. These characteristics of drug addiction have led to a reconsideration of drug addiction as more than simply a homeostatic dysregulation of emotional function, but rather as a dynamic break with homeostasis of these systems termed allostasis (Koob and Le Moal, 2001; Koob and Le Moal, 2008). The hypothesis outlined here is that drug addiction represents a break with homeostatic brain regulatory mechanisms that regulate the emotional state of the animal. Allostasis is defined as stability through change with an altered set point (Sterling and Eyer, 1988) and involves a feed-forward mechanism rather than the negative feedback mechanisms of homeostasis. A feed-forward mechanism has many advantages for meeting environmental demands. For example, in homeostasis, when increased need produces a signal, negative feedback can correct the need, but the time required may be long and the resources may not be available. Continuous reevaluation of need and continuous readjustment of all parameters toward new set points is hypothesized to occur in allostasis. This ability to mobilize resources quickly and to use feed-forward mechanisms may lead to an allostatic state if the systems do not have sufficient time to reestablish homeostasis. An allostatic state can be defined as a state of chronic deviation of the regulatory system from its normal (homeostatic) operating level.

The hypothesis outlined here is that brain stress systems respond rapidly to anticipated challenges to homeostasis (excessive drug taking) but are slow to habituate or do not readily shut off once engaged (Koob, 1999). Thus, the very physiological mechanism that allows a rapid and sustained response to environmental challenge becomes the engine of pathology if adequate time or resources are not available to shut off the response. The interaction between CRF and norepinephrine in the brainstem and basal forebrain, with contributions from other brain stress systems, could lead to the chronic negative emotional-like states associated with addiction (Koob and Le Moal, 2001).

Such negative emotional states are dramatically engaged during acute withdrawal from chronic drugs of abuse but are also chronically “sensitized” in two domains associated with relapse to drug-seeking. The first domain is the construct of protracted abstinence. Numerous symptoms characterized by negative emotional states persist long after acute withdrawal from drugs of abuse. Protracted alcohol abstinence, for example, has been extensively characterized in humans, in which fatigue, tension, and anxiety have been reported to persist from 5 weeks post-withdrawal to up to 9 months (Roelofs, 1985; Alling et al., 1982). These symptoms, post-acute withdrawal, tend to be affective in nature and subacute and often precede relapse (Hershon, 1977; Annis et al., 1998). A leading precipitant of relapse is negative affect (Zywiak et al., 1996; Lowman et al., 1996). In a secondary analyses of patients in a 12 week clinical trial with alcohol dependence and not meeting criteria for any other DSM-IV mood disorder, the association with relapse and a subclinical negative affective state was particularly strong (Mason et al., 1994). Animal work has shown that prior dependence lowers the “dependence threshold” such that previously dependent animals made dependent again display more severe physical withdrawal symptoms than groups receiving alcohol for the first time (Branchey et al., 1971; Baker and Cannon, 1979; Becker and Hale, 1989; Becker, 1994). A history of dependence in male Wistar rats can produce a prolonged elevation in ethanol self-administration after acute withdrawal and detoxification (Roberts et al., 2000; Rimondini et al., 2002, 2008; Sommer et al., 2008). The increase in self-administration is also accompanied by increased behavioral responsivity to stressors and increased responsivity to antagonists of the brain CRF systems (Valdez et al., 2003, 2004; Gehlert et al., 2007; Sommer et al., 2008).

The second domain is the increased sensitivity to reinstatement of drug-seeking behavior shown in stress-induced reinstatement. A variety of stressors, both in humans and animals, will reinstate drug-seeking. In animals, typically the drug-seeking is extinguished by repeated exposure to the drug-seeking environment without drug and in operant situations repeated exposure to the operant response without drug. A stressor, such as footshock, social stress, or pharmacological stress (e.g., yohimbine), reinstates drug-seeking behavior. The neural circuitry of stress-induced reinstatement has significant overlap with that of acute motivational withdrawal described above (Shaham et al., 2003). A history of dependence increases stress-induced reinstatement (Liu and Weiss, 2002).

Repeated challenges (e.g., excessive use of drugs of abuse) lead to attempts of the brain via molecular, cellular, and neurocircuitry changes to maintain stability but at a cost. For the drug addiction framework elaborated here, the residual deviation from normal brain emotional regulation (i.e., the allostatic state) is fueled by numerous neurobiological changes, including decreased function of reward circuits, loss of executive control, facilitation of stimulus–response associations, and notably recruitment of the brain stress systems described above. The compromised brain stress systems are further hypothesized to contribute to the compulsivity of drug-seeking and drug-taking and relapse to drug-seeking and drug-taking known as addiction (Koob, 2009).

10. Summary and conclusions

Acute withdrawal from all major drugs of abuse increases reward thresholds, anxiety-like responses, and CRF in the amygdala, each of which have motivational significance. Compulsive drug use associated with dependence is mediated by not only loss of function of reward systems but also recruitment of brain stress systems such as CRF and norepinephrine in the extended amygdala. Brain arousal/stress systems in the extended amygdala may be key components of the negative emotional states that drive dependence on drugs of abuse and may overlap with the negative emotional components of other psychopathologies.

Acknowledgments

This is publication number 19930 from The Scripps Research Institute. Research was supported by the Pearson Center for Alcoholism and Addiction Research and National Institutes of Health grants AA06420 and AA08459 from the National Institute on Alcohol Abuse and Alcoholism, DA04043 and DA04398 from the National Institute on Drug Abuse, and DK26741 from the National Institute of Diabetes and Digestive and Kidney Diseases. The author would like to thank Mike Arends for his help with manuscript preparation.

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Chronic Stress, Drug Use, and Vulnerability to Addiction (2008)

COMMENT: Stress can increase vulnerability to addiction. Stress can increase vulnerability to addiction, including porn addiction
Chronic Stress, Drug Use, and Vulnerability to Addiction

Rajita Sinha Ann N Y Acad Sci. Author manuscript; available in PMC 2009 August 26. Published in final edited form as: Ann N Y Acad Sci. 2008 October; 1141: 105–130. doi: 10.1196/annals.1441.030. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA Address for correspondence: Rajita Sinha, Ph.D., Professor, Department of Psychiatry, Director, Yale Interdisciplinary Stress Center, Yale University School of Medicine, 2 Church Stress South, Suite 209, New Haven, CT 06515. Voice: +203−974−9608; fax: +203−974−7076. Email: rajita.sinha@yale.edu

Abstract
Stress is a well-known risk factor in the development of addiction and in addiction relapse vulnerability. A series of population-based and epidemiological studies have identified specific stressors and individual-level variables that are predictive of substance use and abuse. Preclinical research also shows that stress exposure enhances drug self-administration and reinstates drug seeking in drug-experienced animals. The deleterious effects of early life stress, child maltreatment, and accumulated adversity on alterations in the corticotropin releasing factor and hypothalamic-pituitary-adrenal axis (CRF/HPA), the extrahypothalamic CRF, the autonomic arousal, and the central noradrenergic systems are also presented. The effects of these alterations on the corticostriatal-limbic motivational, learning, and adaptation systems that include mesolimbic dopamine, glutamate, and gamma-amino-butyric acid (GABA) pathways are discussed as the underlying pathophysiology associated with stress-related risk of addiction. The effects of regular and chronic drug use on alterations in these stress and motivational systems are also reviewed, with specific attention to the impact of these adaptations on stress regulation, impulse control, and perpetuation of compulsive drug seeking and relapse susceptibility. Finally, research gaps in furthering our understanding of the association between stress and addiction are presented, with the hope that addressing these unanswered questions will significantly influence new prevention and treatment strategies to address vulnerability to addiction.

Introduction
Stress has long been known to increase vulnerability to addiction. The last decade has led to a dramatic increase in understanding the underlying mechanisms for this association. Behavioral and neurobiological correlates are being identified, and some evidence of molecular and cellular changes associated with chronic stress and addiction has been identified. Human studies have benefited from the emergence of sophisticated brain-imaging tools and the cross examination of laboratory-induced methods of stress and craving and their association to specific brain regions associated with reward and addiction risk. This paper focuses primarily on the association between stress and addiction in humans but also draws from the broader animal literature to support the proposed hypotheses. A definition of stress and its neural underpinnings is presented with specific emphasis on its effects on motivation and behavior. In the context of strong epidemiological evidence linking early-childhood and adult adversity and risk of addiction, results from basic and human research that point to putative mechanisms underlying this association are presented. A critical role is seen for prefrontal circuits involved in adaptive learning and executive function, including controlling distress and desires/impulses, in the association between stress and addiction risk. However, several questions remain unanswered in understanding stress-related addiction risk, and these are reviewed in order to inform future research. Finally, the effects of chronic drug use on stress and reward pathways particularly with respect to relapse risk are examined. Future directions in addressing stress-related relapse risk in clinical settings are also discussed.

Stress, Emotions, and Adaptive Behavior
The term “stress” refers to processes involving perception, appraisal, and response to harmful, threatening, or challenging events or stimuli.1–3 Stress experiences can be emotionally or physiologically challenging and activate stress responses and adaptive processes to regain homeostasis.2,4–6 Examples of emotional stressors include interpersonal conflict, loss of relationship, death of a close family member, and loss of a child. Common physiological stressors are hunger or food deprivation, sleep deprivation or insomnia, extreme hyper- or hypothermia, and drug withdrawal states. In addition, regular and binge use of many psychoactive drugs serve as pharmacological stressors. This kind of conceptualization allows the separate consideration of (1) internal and external events or stimuli that exert demands or load on the organism; (2) the neural processes that evaluate the demands and assess availability of adaptive resources to cope with the demands (appraisal); (3) the subjective, behavioral, and physiological activity that signal stress to the organism; (4) neuroadaptations in emotional and motivational brain systems associated with chronic stress; and (5) behavioral, cognitive, and physiological adaptation in response to stressors.
While stress is often associated with negative affect and distress, it can include “good stress” which is based on external and internal stimuli that are mild/moderately challenging but limited in duration and results in cognitive and behavioral responses that generate a sense of mastery and accomplishment, and can be perceived as pleasant and exciting.1,3,6,7 Such situations rely on adequate motivational and executive functioning to achieve goal-directed outcomes and homeostasis.3,6,8 However, the more prolonged, repeated, or chronic the stress—for example, states associated with increased intensity or persistence of distress—the greater the uncontrollability and unpredictability of the stressful situation, lower the sense of mastery or adaptability, and greater the magnitude of the stress response and risk for persistent homeostatic dysregulation.1,6,9–11 Thus, the dimensions of intensity, controllability, predictability, mastery, and adaptability are important in understanding the role of stress in increasing risk of maladaptive behaviors such as addiction.

The perception and appraisal of stress relies on specific aspects of the presenting external or internal stimuli, personality traits, availability of internal resources (including physiological condition of the individual), prior emotional state (including beliefs and expectancies), and specific brain regions mediating the appraisal of stimuli as distressing, and the resulting physiological, behavioral, and emotional experiences and adaptive responses. Brain regions such as the amygdala, hippocampus, insula, and orbitofrontal, medial prefrontal, and cingulate cortices are involved in the perception and appraisal of emotional and stressful stimuli, and the brain stem (locus ceruleus and related arousal regions), hypothalamus, thalamus, striatal, and limbic regions are involved in physiological and emotional responses. Together these regions contribute to the experience of distress. Physiological responses are manifested through the two major stress pathways, namely corticotropin releasing factor (CRF) released from the paraventricular nucleus (PVN) of the hypothalamus, which stimulates adrenocorticotrophin hormone from the anterior pituitary, which subsequently stimulates the secretion of cortisol/corticosterone from the adrenal glands, and the autonomic nervous system, which is coordinated via the sympathoadrenal medulary (SAM) systems.4,12

In addition, CRF has extensive influence in extrahypothalamic regions across the corticostriatal-limbic regions and plays a critical role in modulating subjective and behavioral stress responses.13 Furthermore, central catecholamines, particularly noradrenaline and dopamine, are involved in modulating brain motivational pathways (including the ventral tegmental area or VTA, nucleus accumbens [NAc], and the medial prefrontal [mPFC] regions) that are important in regulating distress, exerting cognitive and behavioral control, and negotiating behavioral and cognitive responses critical for adaptation and homeostasis.8,14,15 The hypothalamic and extrahypothalamic CRF pathways and central catechoamines target brain motivational pathways to critically affect adaptive and homeostatic processes. For example, different parts of the medial prefrontal cortex are involved in higher cognitive or executive control functions, such as controlling and inhibiting impulses, regulating distress, focusing and shifting attention, monitoring behavior, linking behaviors and consequences over time, considering alternatives before acting, and decision-making responses.16,17 Psychosocial and behavioral scientists have elegantly shown that with increasing levels of emotional and physiological stress or negative affect, there is a decrease in behavioral control and increases in impulsivity, and with increasing levels of distress, and chronicity of stress, greater the risk of maladaptive behaviors.18–27 Neurobiological evidence shows that with increasing levels of stress, there is a decrease in prefrontal functioning and increased limbic-striatal level responding, which perpetuates low behavioral and cognitive control.28,29 Thus, the motivational brain pathways are key targets of brain stress chemicals and provide an important potential mechanism by which stress affects addiction vulnerability.

Stress and the Development of Addictive Behaviors
There is a substantial literature on the significant association between acute and chronic stress and the motivation to abuse addictive substances (see30 for review). Many of the major theories of addiction also identify an important role of stress in addiction processes. These range from psychological models of addiction that view drug use and abuse as a coping strategy to deal with stress, to reduce tension, to self medicate, and to decrease withdrawal-related distress,31–37 to neurobiological models that propose incentive sensitization and stress allostasis concepts to explain how neuroadaptations in reward, learning, and stress pathways may enhance craving, loss of control, and compulsion, the key components in the transition from casual use of substances to the inability to stop chronic use despite adverse consequences, a key feature of addiction.38–40 In this section, we review the converging lines of evidence that point to the critical role that stress plays in increasing addiction vulnerability.

Chronic Adversity and Increased Vulnerability to Drug Use
There is considerable evidence from population-based and clinical studies supporting a positive association between psychosocial adversity, negative affect, and chronic distress and addiction vulnerability. The evidence in this area can be categorized into three broad types. The first includes prospective studies demonstrating that adolescents facing high recent negative life events show increased levels of drug use and abuse.41–55 Negative life events such as loss of parent, parental divorce and conflict, low parental support, physical violence and abuse, emotional abuse and neglect, isolation and deviant affiliation, and single-parent family structure have all been associated with increased risk of substance abuse.

The second type of evidence is the association between trauma and maltreatment, negative affect, chronic distress, and risk of substance abuse. Overwhelming evidence exists for an increased association between childhood sexual and physical abuse and victimization and increased drug use and abuse.56–60 There is also some evidence that recent negative life events and physical and sexual abuse each exert somewhat independent risk on addiction vulnerability.58 In addition to sexual and physical abuse, negative affect and chronic distress states are predictive of addiction vulnerability. Findings indicate that negative affect, including temperamental negative emotionality, is associated with substance abuse risk.61–67 Several studies have also shown a significant association between prevalence of mood and anxiety disorders, including post-traumatic stress disorder (PTSD), behavioral conduct problems and increased risk of substance use disorders.68–78 As stress is significantly associated with prevalence of mood and anxiety disorders and chronic psychiatric distress,79,80 these associations raise the issue of whether psychiatric disorders conceptualized as chronic distress states may largely account for the significant association between stress and substance use disorders.

In the third type of evidence from population studies, recent research has examined lifetime exposure to stressors and the impact of cumulative adversity on addiction vulnerability after accounting for a number of control factors such as race/ethnicity, gender, socioeconomic status, prior drug abuse, prevalence of psychiatric disorders, family history of substance use, and behavioral and conduct problems.81,82 Cumulative adversity or stress was assessed using a checklist method and by counting the number of different events that were experienced in a given period during the lifespan. The effects of distal (events occurring more than 1 year prior) and proximal stress experiences (events during the most recent 1-year period), and their effects on meeting criteria for substance use disorders were also assessed. The findings indicate that the cumulative number of stressful events was significantly predictive of alcohol and drug dependence in a dose-dependent manner, even after accounting for control factors. Both distal and proximal events significantly and independently affected addiction vulnerability. Furthermore, the dose-dependent effects of cumulative stressors on risk for addiction existed for both genders and for Caucasian, African-American, and Hispanic race/ethnic groups. The types of adverse events significantly associated with addiction vulnerability were parental divorce or conflict, abandonment, forced to live apart from parents, loss of child by death or removal, unfaithfulness of significant other, loss of home to natural disaster, death of a close one, emotional abuse or neglect, sexual abuse, rape, physical abuse by parent, caretaker, family member, spouse, or significant other, victim of gun shooting or other violent acts, and observing violent victimization. These represent highly stressful and emotionally distressing events, which are typically uncontrollable and unpredictable in nature. Table 1 summarizes the types of life events, chronic stressors, maltreatment, and individual level variables associated with addiction risk.

TABLE 1
Types of Adverse Life Events, Trauma, Chronic Stressors, and Individual-Level Variables Predictive of Addiction Risk

Stress Exposure Increases Initiation and Escalation of Drug Self-Administration
There is some evidence from animal studies to support the notion that acute exposure to stress increases initiation and escalation of drug use and abuse (see30,83 for reviews). For example, in animal models, social defeat stress, social isolation, tailpinch and foot-shock, restraint stress, and novelty stress are known to enhance acquisition of opiates, alcohol, and psychostimulant self-administration, with caveats relating to stressor type, genetic background of animals, and variations by drug type (see84–87 for reviews). Also, although there are some negative findings, other evidence indicates that early life stress, using procedures such as neonatal isolation or maternal separation, and prolonged and repeated stressors representing chronic stress experiences, enhances self-administration of nicotine, psychostimulants, and alcohol and/or their acute behavioral effects.88–93 Notably, sex plays an important role in stress-related sensitivity to the reinforcing effects of drugs and in stress enhancement of drug self-administration.93–97 In humans, there is substantial evidence from prospective and longitudinal studies to support the effects of stress on drug use initiation and escalation in adolescents and young adults.24,98–109 Furthermore, there are sex differences in the effects of early trauma and maltreatment on the increased risk of addiction.74,110–114 Laboratory studies examining effects of stress exposure on drug use are limited to legal drugs such as alcohol and nicotine, for ethical reasons. Nonetheless, there is evidence that stress increases drinking and nicotine smoking (see83 for review), but the effects of drinking history, history of adversity, social stress, and expectancies are known to play a role in these experimental studies.

Possible Mechanisms Underlying Stress Effects on Addiction Vulnerability
As evidence using diverse approaches has accumulated in support of a significant effect of stress on risk of addiction, this section examines research on neurobiological links between stress and reward pathways activated by abusive drugs. It is well known that the reinforcing properties of drugs of abuse involve their activation of the mesolimbic dopaminergic (DA) pathways, which include dopamine neurons originating in the ventral tegmental area and extending to the ventral striatum and the prefrontal cortex (PFC).115–117 This pathway is also involved in assigning salience to stimuli, in reward processing, and in learning and adaptation.14,118 Human brain imaging studies also support the role of these systems in drug reward, as psychostimulants, alcohol, opioids, and nicotine all activate the mesolimbic DA systems, in particular, the ventral and dorsal striatum, and such activity has been associated with the drug ratings of high or euphoria and craving.119–126

However, stress exposure and increased levels of glucocorticoids (GC) also enhance dopamine release in the NAc.127–132 Suppression of GC by adrenalectomy reduces extracellular levels of dopamine under basal conditions and in responses to stress and psychostimulants.131,133 However, chronic GC inhibits DA synthesis and turnover in the NAc,134 suggesting that alterations in the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoids can significantly affect DA transmission. There is also evidence that, like drugs of abuse, stress and concomitant increases in CRF and glucocorticoids enhance glutamate activity in the VTA, which in turn enhances activity of dopaminergic neurons.135–138 Human brain imaging studies have further shown that stress-related increases in cortisol are associated with dopamine accumulation in the ventral striatum,125,139 and some evidence also reveals that amphetamine-induced increases in cortisol are associated with both dopamine binding in the ventral striatum and with ratings of amphetamine-induced euphoria.140 Given that both stress and drugs of abuse activate the mesolimbic pathways, it is not surprising that each results in synaptic adaptations in VTA dopamine neurons and in morphological changes in the medial prefrontal cortex.87,136,141,142

In addition to a role in reward, a growing body of human imaging studies and preclinical data indicate that the ventral striatum is also involved in aversive conditioning, in experience of aversive, pain stimuli, and in anticipation of aversive stimuli.143–146 Such evidence points to a role for the mesolimbic dopamine pathways beyond reward processing, and one that more broadly involves motivation and attention to behavioral response during salient (aversive or appetitive) events.147–150 Furthermore, additional regions connected to the mesolimbic DA pathways and involved in reward, learning, and adaptive and goal-directed behaviors are the amygdala, hippocampus, insula, and related corticolimbic regions.118,151 These regions, along with the mesolimbic DA pathways, play an important role in interoception, emotions and stress processing, impulse control and decision making, and in the addictive properties of drugs of abuse.29,152

Stress Mechanisms Involved in Acquisition of Drug Self-Administration
Research has also examined whether stress-related increases in acquisition of drug self-administration are mediated by corticosterone (cortisol in humans). Findings indicate that HPA-activated corticosterone release is important for acquisition of drug self-administration.131,153–155 Corticosterone administration also facilitates psychomotor stimulant effects of cocaine and morphine.156 Furthermore, GC receptor antagonists injected into the VTA decrease morphine-induced locomotor activity,157 suggesting that activity of GC receptors in the VTA could mediate dopamine-dependent behavioral effects. Mice with deletion of the GR gene show a dose-dependent decrease in motivation to self-administer cocaine.158 These data suggest that HPA-related corticosterone release could at least partially mediate the dopamine increases seen after drug administration.

Although in nonhuman primates the link between cortisol, dopamine, and drug self-administration has not been reported, there is evidence that stress related to social subordination is associated with lower levels of D2 receptors and higher cocaine self-administration.159 In humans, positive emission tomography (PET) studies using [11C]raclopride indicate that acute stress exposure increases dopamine release in the ventral striatum (VS). For example, in a small-sample study, Pruessner and colleagues (2004)139 found that healthy individuals with low early-life maternal care showed greater dopamine release in the ventral striatum during an acute psychological stress task as compared to those with a history of high early-life maternal care. Furthermore, cortisol response during the stress task was correlated significantly (r = .78) to VS dopamine release. Oswald and colleagues (2005)125 also demonstrated that acute amphetamine challenge-related subjective “high” responses and concomitant increase in dopamine in the VS were each significantly associated with amphetamine-induced cortisol responses. More recently, the same group has also shown a similar significant relationship between cortisol levels and dopamine release in the VS using a psychological stress task.140 Although these data support the link between stress/cortisol and dopamine transmission, human research linking stress-induced changes in VS activity or dopamine binding and risk of addictive behavior is needed to directly establish the association between stress, mesolimbic dopamine, and addiction risk.

Early Life and Chronic Stress, Dopamine Systems, and Drug Self-Administration
There is growing evidence from basic science studies that early-life stress and chronic stress significantly affect the mesolimbic dopamine pathways and play a role in drug self-administration. Repeated and prolonged exposure to maternal separation (MS) in neonatal rats significantly alters the development of central CRF pathways.11 These animals as adults show exaggerated HPA and behavioral responses to stress.160,161 Such physiological and behavioral changes are associated with altered CRF mRNA expression in the PVN, increased CRF-like immunoreactivity in the locus ceruleus (LC), and increased CRF receptor levels in the LC and raphe nuclei.11 The adult animals also show decreased negative feedback sensitivity to glucocorticoids,162 and these changes are accompanied by decreased GC receptor expression in the hippocampus and frontal cortex.11,163 Decreased GABA receptor levels in noradrenergic cell body regions in the LC and decreased central benzodiazepine (CBZ) receptor levels in the LC and the amygdala have also been reported.164 More importantly, MS rats show significantly elevated DA responses to acute stress along with increased stress-induced behavioral sensitization and robust behavioral sensitization to psychostimulant administration.11,143,165 This cross-sensitization of stress and drugs of abuse is associated with enhanced release of DA in the NAc, lower NAc-core, and striatal DA transporter sites, and reduced D3 receptor binding sites and mRNA levels in the NAc shell.166–168 In addition, chronic norepinephrine deficiency induces changes similar to sensitization that could be related to alterations in DA-signaling pathways.169,170

Early-life stress and prolonged and repeated stress also adversely affect development of the prefrontal cortex, a region that is highly dependent on environmental experiences for maturation.171 The PFC, and particularly the right PFC, plays an important role both in activating the HPA axis and autonomic responses to stress and in regulating these responses.171 For example, lesions of the ventromedial PFC result in enhanced HPA and autonomic responses to stress. High levels of glucocorticoid receptors are also found in the PFC, and chronic GC treatment results in a dramatic dendritic reorganization of PFC neurons similar to that seen in the hippocampus.172,173 Furthermore, early postnatal MS and social isolation result in abnormally high synaptic densities in the PFC and altered densities of DA and serotonin (5-HT) terminals throughout the medial PFC.174 Social defeat stress also alters feedback from the PFC and contributes to drug self-administration.84 Human studies on the neurobiological effects of child maltreatment document neuroendocrine changes as well as alterations in size and volume of prefrontal, thalamic, and cerebellar regions associated with maltreatment and with initiation of addiction.175,176 Together, the data presented in this section highlight the significance of stress effects on mesolimbic and prefrontal regions involved in stress related behavioral control.

Stress, Self-Control, and Addiction Vulnerability
High emotional stress is associated with loss of control over impulses and an inability to inhibit inappropriate behaviors and to delay gratification.20,177,178 Neurobiological data indicate that stress impairs catecholamine modulation of prefrontal circuits, which in turn impairs executive functions like working memory and self-control.17,28,179 There is also growing evidence that adolescents at risk for substance abuse who have experienced several of the stressors listed in Table 1 are more likely to show decreased emotional and behavioral control, and decreased self-control is associated with risk of substance abuse and other maladaptive behaviors.104,152,180,181 Adolescents at risk for substance abuse are known to have decreased executive functioning, low behavioral and emotional control, poor decision making, and greater levels of deviant behavior and impulsivity.24,152,182–184 The corticostriatal-limbic dopamine pathways have been associated with impulsivity, decision making, and addiction risk,185,186 and as discussed in previous sections, specific regions of this pathway, such as the VTA, NAc, PFC, and amygdala, are highly susceptible to stress-related signaling and plasticity associated with early-life stress and chronic stress experiences. In a recent PET imaging study, Oswald (2007)187 examined the effects of chronic stress and impulsivity on amphetamine-induced striatal dopamine release. These findings indicated that high trait impulsivity was associated with blunted right VS dopamine release. However, these effects were modified by a significant interaction with chronic life events stress. With low to moderate stress, dopamine release was greater in low than in high impulsive subjects, but with high stress, both groups showed low DA release. These findings demonstrate the important effects of stress and impulsivity on mesolimbic dopamine transmission and highlight the fact that both factors need to be carefully considered to fully understand the role of stress and impulsivity on addiction risk.

Schematic Model of Stress Effects on Addiction
Figure 1 presents a schematic model of stress effects on addiction. It highlights cross-sensitization of stress and drug abuse on specific behavioral and neurochemical responses and indicates the common neurobiological pathways upon which both stress and drugs of abuse act. Column A lists three types of vulnerability factors: (1) developmental/individual-level factors such as frontal executive function development, negative emotionality, behavioral/self-control, impulsivity, or risk taking, and altered initial sensitivity to rewarding effects of drugs; (2) stress-related vulnerability factors such as early adverse life events, trauma and child maltreatment experiences, prolonged and chronic stress experiences; and (3) genetic influences and family history of psychopathology and addiction, which have not been discussed here but have significant interactive effects on addiction risk and in emotion and stress markers.188–194 Each of these factors may influence each other to significantly affect alterations in neurobiological pathways involved in stress regulation and cognitive and behavioral control (column B). Specific synaptic changes in these pathways at molecular and cellular levels118,195 provide the basis for the mechanism by which stress and individual and genetic factors in column A interact to increase risk of maladaptive behaviors represented in column C. The model suggests that stress experiences in the presence of these vulnerability factors result in maladaptive stress and self-control responses that increase addiction risk. The specific mechanism by which the maladaptive stress responding increases this risk involves dysregulation in brain stress circuits, particularly the CRF and NE systems, and their interactions with the mesocorticolimbicstriatal dopamine pathways and its modulation by glutamate and GABA.114,196,197 Furthermore, recent evidence suggests that stress regulatory molecules, including neuropeptides such as neuropeptide (NPY) endocannabinoids, and neuroactive steroids play a role in addiction vulnerability.198–203

Figure 1(MISSING)
A schematic model of stress effects on addiction, representing the cross-sensitization of stress and drugs on behavioral and neurochemical responses, that are mediated by the stress and reward pathways. Column A lists three types of vulnerability factors: (1) developmental/individual-level factors such as frontal executive function development, negative emotionality, behavioral/self control, impulsivity or risk taking, and altered initial sensitivity to rewarding effects of drugs; (2) stress-related vulnerability factors such as early adverse life events, trauma and child maltreatment experiences, prolonged and chronic stress experiences; and (3) genetic influences and family history of psychopathology. Each of these factors influences each other to significantly affect alterations in neurobiological pathways involved in stress regulation and cognitive and behavioral control (Column B). Such changes at least partially mediate the mechanisms by which stress and individual and genetic factors in column A interact to increase risk of maladaptive behaviors represented in column C when an individual is faced with stress or challenge situations.

Drug Use and Abuse and Changes in Stress and Reward Pathways
Acute and Chronic Drug Use and Changes in Stress Responses
Acute administration of the most commonly abused drugs such as alcohol, nicotine, cocaine, amphetamines, and marijuana that activate brain reward pathways (mesocorticolimbic dopaminergic systems) also activate brain stress pathways (CRF-HPA axis and the autonomic nervous system pathways) with increases in plasma adrenocorticotropic hormone (ACTH) and corticosterone, changes in heart rate and blood pressure, and skin conductance responses.204–217 On the other hand, acute exposure to opiates decreases cortisol levels in humans.218,219 Regular and chronic use of these drugs is also associated with adaptations in these systems that are specific by drug. For example, changes in heart rate and heart rate variability (HRV) are reported with regular and chronic alcohol use.220–222 Sustained increases in HPA axis function in the case of psychostimulants, and tolerance to the inactivating effects of the drug in the case of morphine, nicotine, and alcohol has also been reported.223–226 These direct effects of drugs of abuse on major components of the physiological stress response support their classification as pharmacological stressors.

Acute withdrawal states are associated with increases in CRF levels in CSF, plasma ACTH, cortisol, norepinephrine (NE), and epinephrine (EPI) levels.38,211,216,227–231 Early abstinence is associated with high basal cortisol responses and a blunted or suppressed ACTH and cortisol response to pharmacological and psychological challenges in alcoholics and chronic smokers, while hyper-responsivity of HPA hormones in response to metyrapone has been reported in opiate and cocaine addicts.232–236 Furthermore, withdrawal and abstinence from chronic alcohol is also associated with altered sympathetic and parasympathetic responses,234,237–239 and altered noradrenergic responses to yohimbine challenge in early abstinence from cocaine has also been observed.240 All of the above changes highlight the significant effects of drug use and abuse on physiological stress responses.

Although acute administration of drugs increases mesolimbic dopamine,241 regular and chronic use of abusive drugs and acute withdrawal states down regulate mesolimbic dopamine pathways with decreases in basal and stimulated dopamine reported in several preclinical studies.242–251 Chronic use of cocaine has also been shown to dramatically alter central noradrenergic pathways in the ventral and dorsal striatum, other areas of the fore-brain, and the ventromedial prefrontal cortex.252,253 Human brain imaging studies corroborate these preclinical data, with reduced D2 receptors and dopamine transmission in the frontal and ventral striatum regions in alcoholics and cocaine abusers during acute withdrawal and protracted withdrawal (up to 3−4 months).254–256 Furthermore, blunted dopamine release in the ventral striatum and anterior caudate was associated with a preference to self-administer cocaine over receiving money in human cocaine abusers.257 These changes are similar to the effects of prolonged and repeated stressors on mesolimbic dopamine and norepinephrine deficiency noted in the previous section134,187,258 and raise the question whether chronic drug effects on extrahypothalamic CRF, noradrenergic, or glucocorticoid systems may at least partially modulate these dopamine-related changes in the corticostriatal limbic dopamine pathways.

On the other hand, acute, regular, and chronic exposure to drugs results in “sensitization” or enhanced behavioral and neurochemical response to drugs and to stress. Synaptic alterations in the VTA, NAc, and medial PFC modulated by glutamate effects on dopamine neurons and CRF and noradrenergic effects on DA and non-DA pathways contribute to behavioral sensitization of stress and drugs of abuse.210,259–262 In addition, increased levels of brain derived neurotrophic factor (BDNF) in the mesolimbic dopamine regions has been associated with increases in drug seeking during abstinence from chronic drug use.263,264 Furthermore, behavioral sensitization observed with drugs of abuse and with stress are associated with synaptic changes in mesolimbic dopamine regions, particularly the VTA, NAc, and amygdala, and such changes contribute to compulsive drug seeking.118,265 Thus, there are significant physiological, neurochemical, and behavioral alterations in stress and dopaminergic pathways associated with chronic drug use, which in turn could affect craving and compulsive seeking, maintenance of drug use, and relapse risk. It is not entirely clear how long these changes persist or the extent to which there is recovery or normalization of these pathways and responses in related functional responses.

Altered Stress Responses and Craving with Chronic Drug Abuse
Clinical symptoms of irritability, anxiety, emotional distress, sleep problems, dysphoria, aggressive behaviors, and drug craving are common during early abstinence from alcohol, cocaine, opiates, nicotine, and marijuana.30,266–269 A mild “negative affect” and craving state ensues postwithdrawal, associated with alterations in the stress and dopamine pathways.37,197,250,270 The severity of the these symptoms has been associated with treatment outcomes, with greater dependence and abstinence severity predictive of worse treatment outcomes.271–274 Drug craving or “wanting” for drug is conceptually different from other anxiety and negative affect symptoms as it comes from “desire” or a wish for a hedonic stimulus. However, with chronic drug use, the term becomes associated with a physiological need, hunger, and strong intent to seek out the desired object, thereby representative of the more compulsive aspects of craving and drug seeking identified by addicted patients.274–277 In particular, craving and compulsive seeking is strongly manifested in the context of stress exposure, drug-related cues, and drug itself and can become a potent trigger for relapse.30,274,278–281 Several recent models of addiction have presented the concept that this heightened craving or wanting of drug is the behavioral manifestation of molecular and cellular changes in the stress and dopamine pathways discussed in the previous section. Indeed some support for this idea comes from laboratory and imaging studies summarized below.

In my laboratory, we have examined the effects of stress and drug-related cues on drug craving in alcoholics, cocaine-dependent individuals, and naltrexone-treated, opiate-dependent individuals in recovery. Drug craving and stress responses were assessed in treatment-engaged, abstinent, addicted individuals who were exposed to stressful and nonstressful drug-cue situations and neutral relaxing situations, using personalized guided imagery procedures as the induction method.282 Our initial findings indicated that in addicted individuals, stress imagery elicited multiple emotions of fear, sadness, and anger as compared to the stress of public speaking, which elicited increases in fear but no anger or sadness. In addition, imagery of personal stressors produced significant increases in cocaine craving, while public speaking did not.283–285 Significant increases in heart rate, salivary cortisol, drug craving, and subjective anxiety were also observed with imagery exposure to stress and nonstress drug cues as compared to neutral relaxing cues in cocaine-dependent individuals.285 More recently, we have shown that stress and alcohol/drug-related stimuli similarly increase craving, anxiety, negative emotions, and physiological responses in abstinent alcoholics and in naltrexone-treated, opiate-addicted individuals.286,287 On the other hand, recently abstinent alcoholics and smokers show altered basal HPA responses and a suppressed HPA response as measured by cortisol to stress compared to their nonaddicted counterparts.288–290

In a more comprehensive assessment of the biological stress response in recently abstinent cocaine-addicted individuals, we reported that brief exposure to stress and to drug cues as compared to neutral relaxing cues activated the HPA axis (with increases in ACTH, cortisol, and prolactin levels) as well as the sympthoadrenomedullary systems, as measured by plasma norepinephrine and epinephrine levels.282 Furthermore, we found little evidence of recovery or return to baseline in ACTH, NE, and EPI levels even more than 1 h after the 5-min imagery exposure. These findings were extended to directly compare abstinent cocaine-dependent individuals to a demographically matched group of healthy social drinkers, using individually calibrated personally emotional stress and drug/alcohol cue-related imagery compared to neutral imagery. Findings indicated that cocaine patients showed an enhanced sensitivity to emotional distress and physiological arousal and higher levels of drug craving to both stress and drug-cue exposure compared to controls.291 Similarly, we also compared 4-week abstinent alcoholics to matched social drinkers. The recovering alcoholics at 4 weeks abstinence showed greater levels of basal heart rate and salivary cortisol levels compared to control drinkers. Upon stress and alcohol-cue exposure, they showed persistently greater subjective distress, alcohol craving, and blood pressure responses, but a suppressed heart rate and cortisol response compared to controls.239 Interestingly, both cocaine patients and alcoholics show increased anxiety and negative emotions during drug-cue exposure, while social drinkers report lower levels of negative affect and anxiety with alcohol-cue exposure. These data provide direct evidence of high drug craving and altered hedonic responses to both stress and drug cues in addicted individuals compared to social drinkers (see Fig. 2). They also indicate that alterations in physiological stress responses are associated with high levels of stress-induced and cue-induced craving and distress states. The nature of the alterations are marked by increased emotional distress, heightened craving, altered basal responses, and blunted or suppressed physiological responses in abstinent addicted individuals compared to social drinkers.

Figure 2 (MISSING)
Mean and standard errors for peak craving and anxiety ratings during exposure to stress, drug cues, and neutral imagery conditions. (A) Peak craving is significantly higher in abstinent alcoholics and cocaine patients compared to social drinkers (P

Many studies have also examined brain regions associated with craving in addicted individuals. Exposure to drug cues known to increase craving increases activity in the amygdala and regions of the frontal cortex,292–294 with gender differences in amygdala activity and frontal cortex response in cocaine-dependent individuals.295,296 Cue-induced craving for nicotine, methamphetamine, or opiates also activates regions of the prefrontal cortex, amygdala, hippocampus, insula, and VTA (see Ref. 297). As stress also increases drug craving, we examined brain activation during stress and neutral imagery in a functional magnetic resonance imaging (fMRI) study. Although healthy controls and cocaine-dependent individuals showed similar levels of distress and pulse changes during stress exposure, brain response to emotional stress in paralimbic regions such as the anterior cingulate cortex, hippocampus, and parahippocampal regions was greater in healthy controls during stress, while cocaine patients showed a striking absence of such activation.298 In contrast, cocaine patients had increased activity in the caudate and dorsal striatum region during stress that was significantly associated with stress-induced cocaine craving ratings.

Recent PET studies have also shown significant positive correlations between the dorsal striatum and drug cue–induced cocaine craving.299,300 These findings are consistent with imaging studies with alcoholic patients showing increased association between dorsal striatum regions and alcohol craving in response to presentation of alcohol-related stimuli.301,302 Using PET imaging with alcoholics and cocaine patients, research has shown a significant association between dopamine D2 receptor binding in the VS and drug craving as well as motivation for self-administration.124,303,304 On the other hand, neuropsychological and imaging studies examining prefrontal executive functions, including impulse control, decision making, and set shifting, have shown executive function deficits and hypofrontal responses in addicted individuals compared to control volunteers.305–312 Together, these findings indicate that increased stress and cue-induced craving and compulsive drug-seeking states in addicted individuals are associated with greater activity in the striatum, but decreased activity in specific regions of the cingulate and prefrontal cortex and related regions involved in controlling impulses and emotions.

Stress-Induced Reinstatement of Drug Seeking and Relapse
While several efficacious behavioral and pharmacological therapies in the treatment of addiction exist, it is well known that relapse rates in addiction remain high.30,313,314 Exposure to stress, drug-related stimuli, and drugs themselves each reinstate drug-seeking behavior in animals and increase relapse susceptibility in addicted individuals.274,315–317 Such data underscore the need for specific attention to the chronic relapse susceptibility as a target in addiction treatment development.

In the last decade, a substantial number of preclinical studies have shown that brain CRF, noradrenergic, and glutamatergic pathways contribute to reinstatement of drug seeking.86,316–320 Neuroadaptations associated with chronic drug use include overactive brain CRF and glutamatergic pathways, altered autonomic responses, and underactive dopamine and GABA systems, and these changes may accompany the high craving states and relapse susceptibility associated with the chronic nature of addiction.118,196,197,274,313,321 Furthermore, using animal models of drug self-administration and relapse, preclinical studies have identified CRF antagonists, alpha-2-adrenergic agonists, and more recently, glutamatergic agents as important in reducing stress-induced seeking in addicted laboratory animals (see316,317,322–324). These data are consistent with human findings reviewed in the previous section indicating that alterations in stress and dopaminergic pathways accompany high distress and craving states and blunted physiological and neural responses that are important in regulation of stress, craving, and impulse control.

Human research has also begun to identify markers of the stress and craving states that are predictive of relapse outcomes. To fully understand whether the increased distress and drug-craving state is predictive of relapse, we followed the inpatient treatment-engaged cocaine- and alcohol-dependent individuals in our studies described in previous sections after discharge from inpatient treatment for 90 days to assess relapse outcomes. For the cocaine group, we found that stress-induced cocaine craving in the laboratory significantly predicted time to cocaine relapse. While stress-induced ACTH and cortisol responses were not associated with time to relapse, these responses were predictive of amounts of cocaine consumed during follow-up.325 While drug cue–induced craving was not predictive of relapse in this study, there was a high correlation between stress and drug cue–induced drug craving and in stress and drug cue–induced HPA responses. These data suggest that at least in the case of cocaine dependence, stress and drug cue–induced distress states produce a similar compulsive drug-seeking state that is associated with relapse vulnerability. In alcoholics, negative mood, stress-induced alcohol craving, and blunted stress and cue-induced cortisol responses have been associated with alcohol relapse outcomes.236,326–329 Nicotine-deprived smokers who were exposed to a series of stressors showed blunted ACTH, cortisol, and blood pressure responses to stress but increased nicotine withdrawal and craving scores, and these responses were predictive of nicotine relapse outcomes.289 Thus, for alcoholic and smoking samples, as in the cocaine group, it appears that the drug-craving state marked by increasing distress and compulsive motivation for drug (craving) along with poor stress regulatory responses (altered glucocorticoid feedback or increased noradrenergic arousal) results in an enhanced susceptibility to addiction relapse.

Findings from basic science and human laboratory and clinical outcome studies identify several pharmacological treatment targets to address stress-induced reinstatement of drug seeking and relapse susceptibility. Basic science data suggest CRF antagonists, alpha-2 adrenergic agonists, and glutamatergic agents could be promising in addressing stress-related relapse. Human laboratory studies are needed that will screen these agents to assess their promise with regard to intermediate markers of stress-related relapse susceptibility. Such studies would target stress- and cue-induced drug craving, craving-related anxiety, HPA measures, and heart rate or heart rate variability as well as responses in specific brain regions.297 For example, in a preliminary laboratory and clinical outcomes study, we have shown that lofexidine, an alpha-2 adrenergic agonist, significantly decreased stress-induced opiate craving and stress-induced anger ratings, while also improving opiate relapse outcomes in naltrexone-treated, opiate-dependent individuals.330 Similarly, behavioral strategies that decrease anxiety and stress-related drug craving and normalize stress responses so as to potentiate adaptive responding in high-challenge contexts would be of benefit in decreasing the effects of stress on drug seeking and relapse. For example, mindfulness based stress reduction (MBSR) is efficacious in decreasing relapse to major depression, and adaptations of these strategies could be of benefit to address relapse risk in addiction.274

Summary and Future Directions
This review focuses on the accumulating evidence from preclinical, clinical, and population studies that highly stressful situations and chronic stress increase addiction vulnerability, that is, both risk of developing addiction and risk of relapse. The types of stressors that increase addiction risk are identified in Table 1. The stressors tend to be highly emotionally, distressing events that are uncontrollable and unpredictable for both children and adults. The themes range from loss, violence, and aggression to poor support, interpersonal conflict, isolation, and trauma. There is also evidence for a dose-dependent relationship between accumulated adversity and addiction risk—the greater the number of stressors an individual is exposed to, the higher the risk of developing addiction. Work-related stressors have weaker support, but individual-level variables such as trait negative emotionality and poor self-control (possibly similar to poor executive function) appear to also contribute uniquely to addiction risk. Exposure to such stressors early in life and accumulation of stress (chronicity) result in neuroendocrine, physiological, behavioral, and subjective changes that tend to be long lasting and adversely affect development of brain systems involved in learning, motivation, and stress-related adaptive behaviors. Research that directly addresses stress-related neurobiological changes and their association with behavioral outcomes is sorely needed. Evidence to clarify the contribution of stress to alterations in mesolimbic dopamine activity and its association with drug use is also needed. Figure 1 presents a schematic model of associations that have been supported in research, as well as remaining gaps.

A review of evidence indicating the effects of drug use and abuse on stress responses and dopamine transmission is presented, along with altered emotional and motivational responses associated with craving and relapse to drug use. While substance abuse results in changes in stress and dopaminergic pathways involved in motivation, self control, and adaptive processes necessary for survival, evidence for whether such changes enhance drug seeking or craving and drug use behaviors is lacking. For example, studies on whether prior exposure to licit and illicit drugs modifies the association between stress and drug self-administration are rare. While there are specific neuroadaptations in reward and associated regions, it is also important to examine which of these changes are involved in increasing drug intake and supportive of addictive processes such as progressive loss of control, persistence of craving, and escalating drug self-administration. As stress also increases risk of mood and anxiety disorders that are highly comorbid with addiction, it is important to examine whether there are specific stress-related factors that contribute to risk for mood and anxiety disorders and addiction risk. That is, what are the resiliency factors that are protective for one set of illness but are vulnerabilities for the other. Exploration of gene–environment interactions could be particularly helpful in answering such questions.

A review of recent studies on stress-induced reinstatement to drug seeking, drug craving, and relapse susceptibility is also provided. Clinical implications include the development of new assessment procedures and markers that will be useful in identifying those who are at particular risk for stress-related relapse and testing of novel pharmacological therapies that target the link between stress and relapse risk. As shown in Figure 2, addicted individuals show enhanced sensitivity to craving and greater anxiety in stress- and drug-related situations, but whether such altered responses represent transitions due to chronic drug use or chronic stress states needs to be further examined. Research on the mechanisms by which chronic stress and drug use alter executive functions that are involved in adaptive behavioral responses is needed. Efficacious behavioral treatments focus on improving coping response. However, stress exposure and chronic distress decrease stress adaptive and coping mechanisms, and hence treatments that focus on enhancing coping may not be suitable for those with stress-related risk factors. Development of new interventions that target self-control, especially in the context of stress is needed. Systematic research on these questions will lead to a greater understanding of how stress is associated with relapse. Furthermore, such research may be significant in developing new treatment targets to reduce relapse, both in the area of medication development and in developing behavioral treatments that specifically target the effects of stress on continued drug use and relapse in addicts.

Acknowledgments
Preparation of this review was supported by grants from the National Institutes of Health, P50-DA165556, R01-AA13892, R01-DA18219, and U01-RR24925.
Footnotes
Conflicts of Interest
The author declares no conflicts of interest.

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Cortisol Secretion Patterns In Addiction And Addiction Risk (2006)

Cortisol Secretion Patterns In Addiction And Addiction Risk

William R. Lovallo*
Int J Psychophysiol. 2006 March; 59(3): 195–202.

William R. Lovallo, Behavioral Sciences Laboratories (151A), Veterans Affairs Medical Center, 921 NE 13th Street, Oklahoma City, Oklahoma, 73104, United States;
* Tel.: +1 405 270 0501x3124; fax: +1 405 290 1839. E-mail address: bill@mindbody1.org

Abstract
Addiction to alcohol or nicotine involves altered functioning of the brain's motivational systems. Altered functioning of the hypothalamic–pituitary–adrenocortical (HPA) axis may hold clues to the nature of the motivational changes accompanying addiction and vulnerability to addiction. Alcohol and nicotine show at least three forms of interaction with HPA functioning. Acute intake of both substances causes stress-like cortisol responses. Their persistent use may dysregulate the HPA. Finally, the risk for dependence and for relapse after quitting may be associated with deficient cortisol reactivity to a variety of stressors. The HPA is regulated at the hypothalamus by diurnal and metabolic signals, but during acute emotional states, its regulation is superseded by signals from the limbic system and prefrontal cortex. This top–down organization makes the HPA responsive to inputs that reflect motivational processes. The HPA is accordingly a useful system for studying psychophysiological reactivity in persons who may vary in cognitive, emotional, and behavioral tendencies associated with addiction and risk for addiction. Chronic, heavy intake of alcohol and nicotine may cause modifications in these frontal–limbic interactions and may account for HPA response differences in seen in alcoholics and smokers. In addition, preexisting alterations in frontal–limbic interactions with the HPA may reflect addiction-proneness, as shown in studies of offspring of alcohol- and drug-abusing parents. Continuing research on the relationship between HPA function, stress responsivity, and the addictions may yield insights into how the brain's motivational systems support addictions and risk for addictions.

Keywords: Hypothalamic–pituitary–adrenal axis, Addictions, Nicotine, Alcohol, Cortisol, Stress

1. Introduction
The hypothalamus controls the secretion of cortisol; a hormone necessary for life that regulates the functioning of all cells in the body. The secretion of cortisol is acutely sensitive to inputs from the limbic system and the prefrontal cortex during times of stress. This motivationally relevant communication between the limbic system and the hypothalamic–pituitary–adrenocortical axis (HPA) interacts with alcohol use and abuse in at least three ways. Ingestion of alcohol causes an acute cortisol response. Long-term abuse of alcohol dysregulates the basal and stress-reactive secretion of cortisol. Genetic propensity for alcohol and drug abuse may be accompanied by a reduced HPA response to stress. This paper reviews the basal and stress-reactive control of the HPA in relation to alcoholism with reference to nicotine and other addictions.

1.1. Diurnal and stress-related regulation of the HPA
Cortisol secretion reflects the activity of the HPA. This activity is driven by diurnal and metabolic inputs as well as by stress responses (De Kloet and Reul, 1987; Linkowski et al., 1993). Cortisol's basal, or diurnal, secretion, shown in Fig. 1, peaks in the morning about the time of awakening and declines gradually through the waking hours to achieve a daily minimum during the first half of the sleep cycle (Czeisler et al., 1976). Cortisol's morning burst is driven by the action of clock genes in the suprachiasmatic nucleus of the hypothalamus initiating neuronal signals to the paraventricular nucleus (PVN) (Linkowski et al., 1993). Specialized PVN neurons respond to these signals. Their axons terminate in the median eminence of the hypothalamus, where they release CRF into the portal circulation, causing the anterior pituitary to secrete adrenocorticotropic hormone (ACTH) into the systemic circulation. ACTH is transported to the adrenal gland where it causes the adrenal cortex to increase the synthesis and release of cortisol into the circulation. This diurnal pattern is modulated throughout the day by metabolic inputs arising in relation to blood glucose levels (Van Cauter et al., 1992). Finally, cortisol helps to regulate its own secretion by exerting negative feedback at the pituitary, hypothalamus, and hippocampus (Bradbury et al., 1994). For these reasons, we refer to this basal pattern of HPA regulation as diurnal and metabolic in nature. Chronic disturbances of this diurnal secretion pattern may reflect disorder at one or more levels in this system.

Fig. 1
The 24-h plasma cortisol secretion curve in humans. The secretion peak occurs near the time of awakening and has a nadir during the first half of the sleep cycle. Minor rises can be seen in relation to meals at midday and early evening.

Since the work of Hans Selye, we have been aware that the HPA is supremely reactive to stressors that challenge the well-being of the organism (Selye, 1936). Stressors form two major classes, those that originate in bodily disturbances, such as hemorrhage, and those that originate as external threats, such as confrontation by a predator. The former may be considered bottom-up stressors because their inputs ascend from the body to the brain. In contrast external threats and psychological distress can be thought of as being top–down in nature; they activate the stress axis because of how they are perceived and interpreted (Lazarus and Folkman, 1984;Lovallo and Gerin, 2003). Psychological stressors gain their influence because of how we interpret them in relation to our long-term plans and expectations about the world (Lazarus and Folkman, 1984). It is noteworthy that cortisol is quite responsive to acute psychological distress, suggesting that the source of HPA activation in such cases must involve connections from the limbic system and prefrontal cortex to the hypothalamus.

Our understanding of cortisol responses to psychological stress was increased by the discovery that cortisol has a widespread system of receptors above the hypothalamus. These are found in the hippocampus, the limbic system, and the prefrontal cortex (McEwen et al., 1968; Sanchez et al., 2000). The distribution of these receptors argues strongly that higher brain centers play a role during the psychological stress response and cause responses of the HPA. In fact, during periods of psychological distress, cortisol's diurnal pattern is overridden by signals to the hypothalamus that originate in the limbic system. The signals arise in the amygdala and the bed nuclei of the stria terminalis, structures that are activated by conditioned and unconditioned stimuli and that convey information having survival value (Amaral et al., 1992; Halgren, 1992; LeDoux, 1993). The amygdala therefore stands at the center of a neural network that generates approach and avoidance reactions to innate and learned stimuli (Rolls and Stringer, 2001). Outputs from the amygdala and bed nuclei interact with nearby structures, such as the nucleus accumbens, that, in turn communicate extensively with the prefrontal cortex (Carboni et al., 2000; Figueiredo et al., 2003; Herman et al., 2003). The bed nuclei also provide the primary inputs to the PVN that generate an HPA response to psychological stress. These frontal–limbic processes therefore form the neurophysiological mechanism through which psychological events can generate cortisol responses (Lovallo and Thomas, 2000). These influences are augmented during periods of psychological stress by norepinephrine inputs that ascend from the locus ceruleus in the brainstem to activate the cerebral cortex and limbic system (Harris and Aston-Jones, 1994; Pacak et al., 1995). The stress response is further integrated across the central nervous system by an extensive system of CRF-secreting neurons found in the cerebral cortex and limbic system (Petrusz and Merchenthaler, 1992). Because of the frontal–limbic origin of psychological stress responses, variations in the acute cortisol response to stress may reveal differences between individuals in their limbic system reactivity and psychological controls over their behavior.

The foregoing indicates that the HPA is responsive to the most fundamental motivational processes, such as seeking food, ingestion of nutrients, metabolic regulation, and threats to well being. Addictions to alcohol, nicotine, and other drugs necessarily involve a reworking of these relationships. We may therefore view altered HPA functioning in substance use disorders to be of prime importance in understanding the underlying brain mechanisms.

Alcoholism is a socially defined construct reflecting a person's progressive loss of behavioral control over use of a socially sanctioned drug (American_Psychiatric_Association, 1994). Use of alcohol and illicit drugs, and to a lesser extent, nicotine addiction may involve: (1) use beyond accepted norms or unsanctioned use; (2) forsaking of usual activities; (3) disruption of family life, employment, and legal difficulties; (4) inability to curtail or stop the activity despite repeated attempts; and (5) withdrawal symptoms on cessation of use. The likelihood that common vulnerabilities underlie various addictions is supported by the high rates of comorbid abuse (Burns and Teesson, 2002; Tapert et al., 2002). The common occurrence of multiple addictions also suggests that common vulnerabilities may underlie any one addiction.

The emerging view of the commonalities among addictions is promoted by research showing that addictions involve genetic and acquired alterations in motivational systems within the brain. In a series of influential papers, George Koob and colleagues showed that reward mechanisms are disrupted in rat strains that are prone to self-administer alcohol and other drugs. This dysregulation is worsened by prolonged low-level exposure to drugs of abuse (Ahmed and Koob, 1998; Koob, 2003; Koob and Bloom, 1988; Koob et al., 1994). In Koob's words, the emotional and motivational apparatus of the brain has been “hijacked” in persons that have become dependent on drugs of abuse (Koob and Le Moal, 1997).

Other studies show pervasive alterations of HPA stress responsivity in relation to drug exposure and addiction (Valdez et al., 2003). These alterations involve changes in dopaminergic and opiodergic regulation of CNS function (Oswald and Wand, 2004). Several findings illustrate these points. First and foremost, acute administration of drugs of abuse often causes an HPA response, leading to increased cortisol secretion (Broadbear et al., 2004; Mendelson et al., 1971). Both behavioral stress and drug withdrawal are interchangeable in their effects, as indexed by their mutual ability to evoke anxiety-like behaviors in rats (Breese et al., 2004). Furthermore, rapid drug withdrawal causes release of CRF in widespread brain regions, precipitating a systemic stress reaction (Rodriguez de Fonseca et al., 1997). Stress by itself increases cocaine cravings in human abusers (Sinha et al., 2000), and it increases drug self-administration in animal models (Piazza and Le Moal, 1998). In turn, self-administration appears to depend on the neural signals generated by cortisol feedback to the central nervous system (CNS), because decreasing the production of CNS glucocorticoid receptors also causes a reduction in cocaine self-administration (Deroche-Gamonet et al., 2003). Acute cortisol administration precipitates craving in cocaine-dependent humans (Elman et al., 2003), again suggesting an active role for the HPA in enhanced drug intake. At this time it is not firmly established whether self-administration and drug cravings reflect: (1) the CRF activation associated with generation of a stress response, or (2) if they depend more on cortisol negative feedback to the CNS that is responsible for regulating the duration and intensity of stress responses, or (3) if the character of this feedback is altered due to glucocorticoid receptor variations.

The interaction between stress and drug self-administration depends on the same dopamine pathway that responds during drug seeking and intake. Both stress and the acute administration of several abused drugs increase the excitability of dopamine neurons originating in the ventral tegmental area of the brainstem (Saal et al., 2003). Glucocorticoid receptor blockade prevents the stress-enhancement of dopamine neuron excitability, although it does not prevent the drug-induced effect on this excitability. This suggests that stress and drugs of abuse may initiate their effects in different ways but that they both act on brain dopamine systems as a common pathway to self-administration (Saal et al., 2003).

The evidence above indicates that the limbic system response to emotional stimuli and HPA responses to stress are both of interest in relation to drug intake, addiction vulnerability, and potential for relapse in humans. Consistent with this brain-based model, there is a tendency for addiction proneness to run in families, suggesting that the genes conferring this increased risk affect the same brain systems that are altered in consequence of addiction (Cloninger, 1987; Cloninger et al., 1981). Studies discussed below indicate the possibility that persons with a family history of alcoholism may have altered central opioid function that affects both the frontal–limbic processes necessary for evaluating events and dopaminergic activity that supports drug self-administration.

There are several lines of evidence that suggest alterations in HPA axis responsiveness in relation to current and past addictions as well as risk for addiction by virtue of a positive family history. Evidence for interaction between HPA function and use of alcohol, nicotine, and illicit drugs begins with the fact that all such substances cause acute HPA responses due to pharmacologic activation (Rivier, 1996). The second point of interaction is that the HPA may plausibly be dysregulated by persistent, high-level use of these substances (Adinoff and Risher-Flowers, 1991). Altered reactivity of the HPA in former abusers or persons at risk for abuse by virtue of a family history may derive from underlying psychobiological characteristics, therefore appearing in the absence of current abuse (Adinoff et al., 2005b; King et al., 2002).

This line of thought begins with findings that acute alcohol administration increases HPA function in rats (Rivier et al., 1984) and humans (Mendelson et al., 1971, 1966). Persons dependent on alcohol, nicotine, and other drugs may show chronic activation of the HPA during periods of heavy intake (Steptoe and Ussher, 2006;Wand and Dobs, 1991) and during withdrawal, with the loss of a normal diurnal secretion pattern for days to weeks afterward (Adinoff and Risher-Flowers, 1991). The usual diurnal pattern is reestablished if abstinence is maintained. Alcoholics regain a relatively normal pattern of diurnal cortisol secretion at about one to four weeks of abstinence (Adinoff et al., 2005a,b; Iranmanesh et al., 1989). However, HPA regulation may not be completely normal even after the diurnal pattern has recovered. Adinoff reported that abstinent alcoholics have a deficient cortisol response to HPA stimulation by CRF (Adinoff et al., 2005a,b).

Consistent with this finding, abstinent alcoholics have a blunted cortisol response to physical and psychological stressors for at least 4 weeks postwithdrawal (Bernardy et al., 1996; Errico et al., 1993; Lovallo et al., 2000; Margraf et al., 1967). In these studies, the controls and patients reported equal amounts of psychological distress in response to the stressor exposure, therefore ruling out differential interpretations or mood responses as causes of the blunted responsivity. Other studies of this type are also in agreement that cortisol responses are reduced to public speaking stress in abstinent users of 3,4-methylenedioxymethamphetamine (‘ecstasy’) (Gerra et al., 2003b) and to negative emotions induced by photographs in abstinent heroin addicts (Gerra et al., 2003a). Abstinent heroin addicts also had reduced cortisol responses during a hostility-inducing game (Gerra et al., 2004). It would appear that abstinent alcoholics, heroin addicts, and users of ecstasy all show a persistent hyporesponsiveness to behavioral stress and related affect inductions. These findings collectively point to a persistent disruption of the usual limbic-system inputs to the hypothalamus in persons with an elevated abuse potential. Because these patients had a prolonged history of alcohol or drug intake, it is unclear if their cortisol response deficits were a consequence of drinking or drug addiction, if HPA responses would recover over time, or if the response deficit points to preexisting alterations of limbic system control over the HPA.

A recent study of abstinent alcoholics provides an alternative perspective (Munro et al., 2005). Similar ACTH and cortisol responses were seen in healthy controls and alcoholics abstinent for an average of 3.5 years and ranging up to 17 years. It is perhaps noteworthy that these alcoholics in remission did not differ from controls in their reported symptoms of depression, a characteristic that differs from most studies of alcoholics. It is not immediately clear if the alcoholics had recovered a normal level of HPA response with prolonged abstinence, if they had been normal all along, or if their lack of psychological comorbidity indicated that they were less affected by secondary characteristics related to a hyporesponsive HPA axis. However, the null results raise helpful questions about possible sources of heterogeneity within the alcoholic population. Variation in HPA response to stress, and to opioid challenge, may be related to comorbid depression or externalizing tendencies, such as novelty seeking (Oswald et al., 2004) and low sociability (Sorocco et al., 2006). This suggests useful avenues for future work on the causes of HPA hyporeactivity in relation to addiction.

The studies showing blunted HPA reactivity in substance use disorders raise the question of whether the reactivity difference is a consequence of addiction or a characteristic of the persons in question. Limited, but suggestive, evidence indicates that a hyporesponsive HPA signals the severity of the underlying addictive process. Alcoholics in treatment tend to relapse more rapidly when they have smaller cortisol responses to public speaking stress (Junghanns et al., 2003) or in response to alcohol cues in a cue exposure procedure (Junghanns et al., 2005). Studies on abstinent smokers, reported in this issue, show that small stress cortisol responses signal greater relapse potential as well (al'Absi, 2006). Relapse was also related to the magnitude of cortisol reduction after cessation from smoking, indicating relatively lower tonic cortisol levels in persons with greater relapse potential (Steptoe and Ussher, 2006).

Studies using the opioid blocking agents, naloxone and naltrexone, provide insight into the nature of the blunted HPA responsiveness observed in alcoholics, and they support the idea that such deficits predate heavy drinking. Wand and colleagues administered intravenous naloxone to nonabusing young adults with (FH+) and without (FH−) a family history of alcoholism and found that the FH+ had a large and rapid cortisol response over the next 120 min, compared to the FH− (Wand et al., 1998). Other tests ruled out peripheral response differences as a source of these findings (Oswald and Wand, 2004). King also has reported that oral naltrexone causes larger and more prolonged cortisol responses in FH+ than in FH− (King et al., 2002). Her FH+ subjects reported a greater decline in feelings of vigor, again pointing to central nervous system effects of the opioid blockade. These results show altered central regulation of the HPA in FH+ who have no personal history of heavy drinking.

The above studies suggest that attenuated HPA responses in alcoholics may reflect a difference that predates their heavy drinking. Fig. 2 is adapted from a model developed by Wand that suggests how opioid-producing neurons may act at the hypothalamus, the prefrontal cortex, and the brainstem to influence HPA responsivity in relation to genetic risk for alcoholism.
(1) Opioid neurons from the arcuate nucleus of the hypothalamus normally inhibit CRF-neurons of the PVN, restraining CRF delivery to the pituitary gland, thereby reducing ACTH and cortisol release, and possibly diminishing stress responsivity. Opioid blockade thus releases the PVN from this tonic restraint, allowing cortisol production to rise.
(2) Opioid neurons in the brainstem normally inhibit the NE-producing cells of the locus ceruleus. Opioid blockade releases the locus ceruleus from this inhibitory influence, allowing NE release to activate the CRF-neurons of the PVN, again allowing cortisol production to increase.
(3) A secondary effect of opioid blockade occurs in the prefrontal cortex. Opioid neurons normally activate DA release in the nucleus accumbens. Opioid blockade reduces this DA release, potentially altering moods and processing of reward information. According to Wand's model, opioid blockade would enhance HPA reactivity, reduce the effectiveness of rewards, and have negative effects on mood (King et al., 2002).

Fig. 2
Effects of opioid blockade on cortisol secretion. Opioid blockade acts in the brain to increase cortisol secretion and alter mood. (1) Opioid neurons from the arcuate nucleus of the hypothalamus normally inhibit CRF output by neurons of the PVN, reducing (more ...)

Wand proposes that opioid blockade may cause greater cortisol effects in FH+ because of a variation in the μ-opioid receptor gene that codes for the production of a high-affinity opioid receptor on CNS neurons (Oswald and Wand, 2004). In a test of this hypothesis, males having one or two copies of the high-affinity allele had a twofold larger cortisol response to opioid blockade than did the subjects having the low-affinity allele. This provides a plausible mechanism for the greater response to opioid blockade seen in FH+, and it is consistent with the blunted stress response seen in recovering alcoholics. Although this model provides a mechanistic framework for the results of the opiate blockade studies, a differential prevalence of the high-affinity allele is not yet established in FH+ persons. The opioid model is appealing because it is testable in humans and animals, and it provides insights into variations in human HPA response, dopamine mechanisms, and genetic susceptibility to addiction.

The finding that young adults with alcoholic fathers have exaggerated HPA responses to opioid blockade raises the question of whether they respond differentially to nonpharmacologic stimuli. Several studies show that psychological stress responses are blunted in adolescents and young adults whose parents have a history of alcoholism. Moss, Vanyukov and colleagues have tested cortisol responses to stress in 10- to 12-year-old boys whose fathers were alcoholics or were addicted to drugs (Moss et al., 1995, 1999). In these studies, the subjects entered the hospital to undergo an event-related-potential study that called for the application of scalp electrodes and attachment to complex equipment. The authors accordingly viewed this as a mildly anxiety-provoking stressor. They sampled cortisol from saliva collected before and after the procedure. The authors interpreted an elevation of cortisol before the procedure to be an anxiety-based, anticipatory stress response. The decline in cortisol after the procedure was taken as a return to an unstressed baseline, used to indicate the size of the stress response. The FH+ boys showed a lower level of cortisol before the procedure and an attenuated decline in cortisol afterward, relative to the FH− group. Followup work with the boys showed that attenuated cortisol responses were associated with greater experimentation with cigarettes and marijuana when the boys were 15 to 16 years of age, regardless of FH category (Moss et al., 1999).

This evidence implicates a family history of substance abuse as a factor predisposing to altered CNS responses to potential threats from the environment, with consequent reductions in cortisol response. These authors also implicate antisocial behavior in the father and in the son as further predictors of a stress hyporeactivity. Boys with more symptoms of conduct disorder and whose fathers displayed more symptoms of antisocial personality disorder had correspondingly reduced cortisol levels and responsivity (Vanyukov et al., 1993), and they had higher levels of predicted risk of future substance use disorder (Dawes et al., 1999). These studies indicate a deficiency in response to potential threats, and they implicate the presence of antisocial tendencies as a contributing characteristic. Antisocial tendencies are indication of reduced emotional response to normally evocative events, they frequent accompany substance use disorders, and they have a known inherited basis (Langbehn et al., 2003).

A recent study directly compared HPA responsivity to opioid blockade vs. response to the psychological distress of public speaking (Oswald et al., 2004). Two findings stood out. First, persons were comparably more or less reactive to both challenges, showing a correlation of r=.57 in ACTH response, indicating strong individual-difference tendencies despite the disparate challenges. Second, the characteristic of novelty seeking predicted this stable difference across subjects. Novelty seeking is part of a dimension of disinhibition that has been related to substance abuse risk in some studies (Cloninger, 1987). However, in this case, persons higher in novelty seeking were more, not less, reactive than those low in this trait. In addition, the risk groups did not differ in cortisol response. This indicates that both ACTH and cortisol should be sampled when feasible in such studies and that externalizing tendencies may predict altered responsivity to both to biological and psychological challenges. This finding should be tested further in persons at familial risk for the disorder.

In work reported in this special issue, we have examined young adult offspring of alcoholic parents and subjected them to psychological stressors in the lab (Sorocco et al., 2006). These subjects were older than the subjects tested by Moss and colleagues, and they were tested on both a day of stress and a day of rest to obtain a well-defined basal cortisol secretion pattern. The subjects were classified as to antisocial tendencies using the Sociability Scale of the California Personality Inventory (Gough, 1994; Kosson et al., 1994). The subgroup that was FH+ and low in sociability had a significantly attenuated stress cortisol response. The results are in broad agreement with the work in adolescents. Two points deserve mention. (1) Much of the reduction in cortisol responsivity in both studies appears to be associated with the antisocial characteristics of the FH+ groups. (2) The followup study found that cortisol itself was the strongest predictor of nicotine and marijuana use (Moss et al., 1999).

Cortisol measured in saliva is ideal for human studies because it may be sampled noninvasively inside and outside the laboratory and in relation to many behavioral states (Kirschbaum and Hellhammer, 1989). The HPA is an important system to examine in relation to familial risk or existing addiction. As Wand notes, “Studying the release of HPA axis hormones provides a window on CNS function and can uncover differences in neurotransmitter systems as a function of both alcoholism and family history of alcoholism” (Oswald and Wand, 2004).

The risk for alcoholism and other forms of substance abuse appears to be greater in persons with a presumed genetic risk for an addictive disorder, as indicated by a family history of such problems. The inherited risk may be tied to alterations of brain systems that form emotional responses to motivationally relevant situations. In particular, persons with a diminished cortisol response to normal threat cues may those at highest risk for future risky experimentation with drugs and alcohol. The fact that a blunted stress cortisol response appears to be more likely to occur in persons with antisocial characteristics further implicates brain motivational systems as a key link to an inherited risk. Cortisol production is both a measure of response and also a powerful source of feedback to relevant brain systems. This feedback itself may modify long-term responsivity of the prefrontal cortex and limbic system. The relative contributions of cortisol's feedforward and feedback roles in the addictions are not yet determined.

Acknowledgments
Supported by the U.S. Department of Veterans Affairs and Grant Nos. AA12207 and M01 RR14467 from the U.S. Public Health Service, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, and National Center for Research Resources, Bethesda, MD, USA.

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Dynamics of Neuronal Circuits in Addiction: Reward, Antireward, and Emotional Memory (2009)

Pharmacopsychiatry. Author manuscript; available in PMC Sep 8, 2009.

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Abstract

Drug addiction is conceptualized as chronic, relapsing compulsive use of drugs with significant dysregulation of brain hedonic systems. Compulsive drug use is accompanied by decreased function of brain substrates for drug positive reinforcement and recruitment of brain substrates mediating the negative reinforcement of motivational withdrawal. The neural substrates for motivational withdrawal (“dark side” of addiction) involve recruitment of elements of the extended amygdala and the brain stress systems, including corticotropin-releasing factor and norepinephrine. These changes, combined with decreased reward function, are hypothesized to persist in the form of an allostatic state that forms a powerful motivational background for relapse. Relapse also involves a key role for the basolateral amygdala in mediating the motivational effects of stimuli previously paired with drug seeking and drug motivational withdrawal. The basolateral amygdala has a key role in mediating emotional memories in general. The hypothesis argued here is that brain stress systems activated by the motivational consequences of drug withdrawal can not only form the basis for negative reinforcement that drives drug seeking, but also potentiate associative mechanisms that perpetuate the emotional state and help drive the allostatic state of addiction.

Conceptual Framework

Drug addiction, also known as substance dependence, is a chronically relapsing disorder characterized by (1) compulsion to seek and take the drug, (2) loss of control in limiting intake, and (3) emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) when access to the drug is prevented (defined here as dependence). Although the emergence of a negative emotional state is not an established criterion of Substance Dependence defined by the Diagnostic and Statistical Manual of Mental Disorder, 4th edition (DSM-IV, [4]), it is a reflection of what has been termed motivational withdrawal. As such, it is one criterion in the DSM-IV and a widespread symptom of addiction [78]. Clinically, the occasional but limited use of an abusable drug is distinct from compulsive drug use and the emergence of chronic drug addiction. An important goal of current neurobiological research is to understand the neuropharmacological and neuroadaptive mechanisms within specific neurocircuits that mediate the transition from occasional, controlled drug use and the loss of behavioral control over drug seeking and drug taking that defines chronic addiction. Drug addiction has been conceptualized as a disorder that progresses from impulsivity to compulsivity in a collapsed cycle of addiction comprised of three stages: preoccupation/anticipation, binge intoxication, and withdrawal/negative affect [41, 44, 45].

Different theoretical perspectives, ranging from experimental and social psychology to neurobiology, can be superimposed on these three stages, which are conceptualized as feeding into each other, becoming more intense, and moving from positive to negative reinforcement. Positive reinforcement can be defined as a situation in which presentation of a stimulus increases the probability of a response, and negative reinforcement can be defined as a situation in which removal of a stimulus increases the probability of a response. Neural substrates for the positive reinforcing properties of drug taking and drug seeking have dominated the field of the neurobiology of addiction. However, more recent work has focused on the negative reinforcement mechanisms associated with removal of a negative emotional state associated with abstinence and protracted abstinence of the withdrawal/negative affect stage and the preoccupation/anticipation stage of the addiction cycle, respectively [34, 37]. The conceptual framework is based on “motivational” aspects of addiction and an emphasis on the transition from drug use to addiction in which emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability; termed the “dark side”) emerges when access to the drug is prevented and provides a key motivational basis for the establishment of addiction and its perpetuation.

Two neurobiological circuits are proposed as key to the hedonic aspects of the motivation to seek drugs: the neurobiological circuitry involved in dysregulation of the positive-reinforcing properties of drugs of abuse (ventral striatal-pallidal-thalamic loops) and the neurobiological circuitry associated with recruitment of the negative-reinforcing properties of drugs of abuse (extended amygdala) (Figure 1). The present review will explore the neurobiological mechanisms of addiction that are involved in various stages of the addiction cycle, with a focus on the plasticity of neurocircuits associated with the transition from drug taking to drug addiction, the motivational effects of withdrawal and protracted abstinence, and the parallels with emotional memory that help sustain the addiction process.

Figure 1 
Neural circuitry associated with the three stages of the addiction cycle, the drugs that are currently in use for the treatment focused on these stages, and the targets identified in this review relevant to these stages. Binge/intoxication stage: Reinforcing ...

Neurocircuitry of Positive Reinforcement that is Dysregulated with Drugs of Abuse

A brain reward system has long been hypothesized since the discovery of electrical brain stimulation reward or intracranial self-stimulation [64] and the discovery that animals will self-administer drugs without a history of dependence [81]. Brain stimulation reward involves widespread neurocircuitry in the brain, but the most sensitive sites defined by the lowest reward thresholds involve the trajectory of the medial forebrain bundle connecting the ventral tegmental area with the basal forebrain [64]. Although much emphasis was focused initially on the role of the ascending monoamine systems in the medial forebrain bundle, other nondopaminergic systems in the medial forebrain bundle clearly have a key role [27]. The interaction of drugs of abuse with the hypothesized reward system was emphasized by the observation that all drugs of abuse, when administered acutely, decrease brain stimulation reward thresholds [47].

The acute reinforcing effects of drugs of abuse are mediated by the activation of dopamine, serotonin, opioid peptides, and γ-aminobutyric acid (GABA) systems, either by direct actions in the basal forebrain (notably the nucleus accumbens and central nucleus of the amygdala) or by indirect actions in the ventral tegmental area [32, 35, 42, 61]. Much evidence supports the hypothesis that the mesolimbic dopamine system is dramatically activated by psychostimulant drugs during limited-access self-administration. Although injections of all drugs of abuse increase extracellular dopamine levels in the nucleus accumbens measured by in vivo microdialysis [14], significantly less of an increase occurs in the nucleus accumbens for ethanol, nicotine, and opioids during self-administration [15, 97]. Additionally, opioid and ethanol self-administration are unaffected by selective destruction of the mesolimbic dopamine system [16, 60, 66, 69]. Serotonin systems, particularly those involving serotonin 5-HT1B receptor activation in the nucleus accumbens, also have been implicated in the acute reinforcing effects of psychostimulant drugs. Opioid peptide receptors in the ventral striatum, ventral tegmental area, and amygdala have been hypothesized to mediate the acute reinforcing effects of opioid and ethanol self-administration, largely based on the effects of opioid antagonists. Opioid antagonists injected into the nucleus accumbens and central nucleus of the amygdala are particularly effective in blocking opioid and ethanol self-administration [28, 92]. GABAergic systems are activated pre- and postsynaptically in the amygdala by ethanol at intoxicating doses, and GABA antagonists injected into the amygdala block ethanol self-administration (for reviews, see [35, 61]).

The neural substrates and neuropharmacological mechanisms for the negative motivational effects of drug withdrawal may involve disruption of the same neurochemical systems and neurocircuits implicated in the positive reinforcing effects of drugs of abuse, termed a within-system neuroadaptation. All drugs of abuse produce elevations in brain reward thresholds during acute withdrawal [43], and in animal models of the transition to addiction, increases in brain reward thresholds (i.e., decreased reward) temporally precede and highly correlate with the increase in drug intake with extended access [1, 31] (Figure 2).

Figure 2Figure 2 
(A) Relationship between elevations in intracranial self-stimulation (ICSS) reward thresholds and cocaine intake escalation. (Left) Percent change from baseline ICSS thresholds. (Right) Number of cocaine injections earned during the first hour of each ...

During such acute withdrawal, decreased activity of the mesocorticolimbic dopamine system occurs, as well as decreased functional activity in opioid peptide, GABA, and glutamate systems in the nucleus accumbens and amygdala. Repeated administration of psychostimulants produces an initial facilitation of dopamine and glutamate neurotransmission in the nucleus accumbens [91, 96]. However, chronic administration leads to decreases in dopaminergic and glutamatergic neurotransmission in the nucleus accumbens during acute withdrawal [29, 97], opposite responses of opioid receptor transduction mechanisms in the nucleus accumbens during opioid withdrawal [84], changes in GABAergic neurotransmission during alcohol withdrawal [25, 71], and differential regional changes in nicotinic acetylcholine receptor function during nicotine withdrawal.

Human imaging studies of addicts during withdrawal or protracted abstinence have provided results that are consistent with animal studies. Dopamine D2 receptors decrease (hypothesized to reflect hypodopaminergic functioning), and hypoactivity of the orbitofrontal-infralimbic cortex system occurs [95]. Decreases in reward neurotransmitter function have been hypothesized to contribute significantly to the negative motivational state associated with acute drug abstinence and may trigger long-term biochemical changes that contribute to the clinical syndrome of protracted abstinence and vulnerability to relapse.

Neurocircuitry of the Negative Reinforcement Associated with Chronic Use of Drugs of Abuse

The dark side of addiction [43] has been hypothesized to involve long-term, persistent plasticity in the activity of neural circuits mediating motivational systems that derive from recruitment of antireward systems that drive aversive states. The withdrawal/negative affect stage defined above consists of key motivational elements, such as chronic irritability, emotional pain, malaise, dysphoria, alexithymia, and loss of motivation for natural rewards, and is characterized in animals by increases in reward thresholds during withdrawal from all major drugs of abuse. Antireward is a concept based on the hypothesis that brain systems are in place to limit reward [41, 45].

The neuroanatomical entity termed the extended amygdala may represent a neuroanatomical substrate for the negative effects on reward function defined as antireward. The extended amygdala is composed of the bed nucleus of the stria terminalis, the central nucleus of the amygdala, and a transition zone in the medial subregion of the nucleus accumbens (shell of the nucleus accumbens). Each of these regions has certain cytoarchitectural and circuitry similarities. The central division of the extended amygdala receives numerous afferents from limbic structures, such as the basolateral amygdala and hippocampus, and sends efferents to the medial part of the ventral pallidum and the lateral hypothalamus, thus further defining the specific brain areas that interface classical limbic (emotional) structures with the extrapyramidal motor system [2].

The neurochemical systems within the extended amygdala that provide the neurochemical basis for antireward may be extensive and reflect a complex buffered system for maintaining hedonic homeostasis [41]. However, a neurochemical focal point for the antireward neurotransmitter systems are corticotropin-releasing factor (CRF), norepinephrine, and dynorphin. CRF, norepinephrine, and dynorphin are recruited during chronic drug exposure, producing aversive or stress-like states during withdrawal [36, 45].

Different neurochemical systems involved in stress modulation may also be engaged within the neurocircuitry of the brain stress systems in an attempt to overcome the chronic presence of the perturbing drug and to restore normal function despite the presence of drug—termed a between-system neuroadaptation. The hypothalamic-pituitary-adrenal axis and the brain stress system, both mediated by CRF, are dysregulated by chronic administration of drugs of abuse, with a common response of elevated adrenocorticotropic hormone and corticosterone and extended amygdala CRF during acute withdrawal from all major drugs of abuse [43, 48]. Acute withdrawal from drugs of abuse may also increase the release of norepinephrine in the bed nucleus of the stria terminalis and decrease functional levels of neuropeptide Y (NPY) in the amygdala [65, 77].

For example, with alcohol, CRF may have a key role in mediating the neuroendocrine, autonomic, and behavioral responses to stress and anxiety that drive excessive drinking during dependence [40]. Regions of the extended amygdala (including the central nucleus of the amygdala) contain high amounts CRF terminals, cell bodies, and receptors and comprise part of the “extrahypothalamic” CRF-stress system [57]. Numerous studies have demonstrated the involvement of the extended amygdala CRF system in mediating the behavioral responses associated with fear and anxiety [40]. During ethanol withdrawal, extrahypothalamic CRF systems become hyperactive, with an increase in extracellular CRF within the central nucleus of the amygdala and bed nucleus of the stria terminalis of dependent rats [19, 58, 65, 99], and this dysregulation of brain CRF systems is hypothesized to underlie both the enhanced anxiety-like behaviors and enhanced ethanol self-administration associated with ethanol withdrawal. Supporting this hypothesis, the subtype nonselective CRF receptor antagonists α-helical CRF9-41 and d-Phe CRF12-41 (intracerebroventricular administration) reduce both ethanol withdrawal-induced anxiety-like behavior and ethanol self-administration in dependent animals [5, 93]. CRF receptor antagonists also attenuate anxiety-like behavior [68] as well as ethanol self-administration in ethanol-dependent rats [19]. Systemic administration of CRF1 antagonists have similar actions on anxiety-like responses associated with acute and protracted abstinence and on ethanol self-administration during acute withdrawal and protracted abstinence [36]. These data suggest an important role for CRF, primarily within the central nucleus of the amygdala, in mediating the increased self-administration associated with dependence. Similar results have been observed with the increased intravenous self-administration associated with extended access to heroin [24], cocaine [85], and nicotine [21].

These results suggest not only a change in the function of neurotransmitters associated with the acute reinforcing effects of drugs of abuse during the development of dependence, such as decreases in dopamine, opioid peptides, serotonin, and GABA function, but also recruitment of the CRF system (Figure 3). Additional between-system neuroadaptations associated with motivational withdrawal include activation of the dynorphin/κ opioid system, activation of the norepinephrine brain stress system, and dysregulation of the NPY brain antistress system [43]. Additionally, activation of the brain stress systems may contribute not only to the negative motivational state associated with acute abstinence, but also to the vulnerability to stressors observed during protracted abstinence in humans. Altogether these neurochemical studies (from addiction neurobiology) and neuroanatomical studies (from behavioral neuroscience) point to a rich substrate for the integration of emotional stimuli related to the “dark side of addiction,” defined as the development of the aversive emotional state that drives the negative reinforcement of addiction.

Figure 3 
Neurocircuitry associated with the acute positive reinforcing effects of drugs of abuse and the negative reinforcement of dependence and how it changes in the transition from nondependent drug taking to dependent drug taking. Key elements of the reward ...

Addiction and Antireward: Fear and Pain

Another compelling argument for the integration of the extended amygdala and emotional states comes from the extensive data from Le Doux and colleagues, whom have shown a convergence of the expression of the conditioned fear response in the central nucleus of the amygdala [50]. Studies on the neurocircuitry of fear conditioning show that auditory stimuli from the auditory cortex and pain from the somatosensory cortex converge on the lateral amygdala, which then projects to the central nucleus of the amygdala to elicit the various autonomic and behavioral responses to conditioned fear [50]. Perhaps even more intriguing is the hypothesis that the central nucleus of the amygdala is a key component of the neurocircuitry involved in emotional pain processing [67]. The spino (trigemino)-ponto-amygdaloid pathway that projects from the dorsal horn to the mesencephalic parabrachial area to the central nucleus of the amygdala has been hypothesized to be involved in emotional pain processing [7]. Under this framework, pain represents a break with homeostatic brain regulatory mechanisms that mediate nociception.

The conditions under which opioids block pain and restore homeostasis would be situations of pain in which the opioid relieves the pain and returns the subject to a homeostatic hedonic state; thus, opponent processes do not need to be engaged. However, if too much opioid is administered, either because of overdosing or pharmacokinetic variables, the body will react to that perturbation with the engagement of opponent processes. Hyperalgesia to opioids may occur in subjects in whom the opioid itself produces a break with homeostasis. Hyperalgesia is much less likely to occur when the opioid is in fact restoring homeostasis. Repeated engagement of opponent processes without time for the system to reestablish homeostasis will engage not only hyperalgesia but also the allostatic process described below. Such processes may be invoked by treating with too high a dose of an opioid, treating with an opioid when the dose overshoots the pain need because of pharmacokinetic issues, and/or treating a subject in whom in fact no pain exists (Koob GF, Shurman J, Gutstein H, unpublished results).

Withdrawal, Protracted Abstinence, and Allostasis

The development of the aversive emotional state that drives the negative reinforcement of addiction has been defined as the “dark side” of addiction [43, 45] and is hypothesized to be the motivational withdrawal component of the hedonic dynamic known as opponent process when the initial drug effect is euphoria. The negative emotional state that comprises the withdrawal/negative affect stage defined above consists of key motivational elements, such as chronic irritability, emotional pain, malaise, dysphoria, alexithymia, and loss of motivation for natural rewards in humans, and is reflected in animal models by increases in anxiety-like behavior, dysphoric-like responses, and reward thresholds during withdrawal from all major drugs of abuse. As noted above, two processes are hypothesized to form the neurobiological basis for motivational withdrawal: loss of function in the reward systems (within-system neuroadaptation) and recruitment of the brain stress or antireward systems (between-system neuroadaptation) [38, 41]. As dependence and withdrawal develop, brain stress systems such as CRF, norepinephrine, and dynorphin are recruited, producing aversive or stress-like states [45]. At the same time, within the motivational circuits of the ventral striatum-extended amygdala, reward function decreases. The combination of decreases in reward neurotransmitter function and recruitment of antireward systems provides a powerful source of negative reinforcement that contributes to compulsive drug-seeking behavior and addiction.

The overall conceptual theme argued here is that drug addiction represents a break with homeostatic brain regulatory mechanisms that regulate the emotional state of the animal. However, the view that drug addiction represents a simple break with homeostasis is not sufficient to explain a number of key elements of addiction. Drug addiction, similar to other chronic physiological disorders such as high blood pressure, worsens over time, is subject to significant environmental influences, and leaves a residual neuroadaptive trace that allows rapid “re-addiction” even months and years after detoxification and abstinence. Relapse, or the return to drug abuse following periods of abstinence, is one of the principle characteristics of substance dependence on alcohol. The development of dependence has been suggested to play an important role in the maintenance of compulsive use and relapse following periods of abstinence.

In human alcoholics, numerous symptoms that can be characterized by negative emotional states persist long after acute physical withdrawal from ethanol. These symptoms, post-acute withdrawal, tend to be affective in nature and subacute and often precede relapse. Negative affective states, including negative emotions such as elements of anger, frustration, sadness, anxiety, and guilt, are the leading precipitants of relapse [53]. This state has been termed “protracted abstinence” and has been defined in humans who exhibit a Hamilton Depression rating ≥8 with the following three items consistently noted by subjects: depressed mood, anxiety, and guilt [53]. For example, fatigue and tension have been reported to persist up to 5 weeks post-withdrawal [3]. Anxiety has been shown to persist up to 9 months [73], and anxiety and depression have been shown to persist in up to 20-25% of alcoholics for up to 2 years post-withdrawal.

Animal work with alcohol dependence has shown that prior dependence can lower the “dependence threshold” such that previously dependent animals made dependent again display more severe physical withdrawal and anxiety-like symptoms than groups receiving alcohol for the first time [6, 8]. This supports the hypothesis that alcohol experience and the development of dependence in particular can lead to relatively permanent alterations in responsiveness to alcohol. However, relapse often occurs even after acute withdrawal signs have subsided, suggesting that the neuropharmacological changes that occur during the development of dependence can persist beyond the final overt signs of withdrawal (“protracted motivational withdrawal syndrome”). Such protracted withdrawal has motivational significance. A history of dependence in rats and mice can produce a prolonged elevation in ethanol self-administration in daily 30 min sessions long after acute withdrawal and detoxification [70, 72]. The increase in self-administration is also accompanied by increased behavioral responsivity to stressors and increased responsivity to CRF receptor antagonists [46]. These persistent alterations in ethanol self-administration and residual sensitivity to stressors can be arbitrarily defined as a state of “protracted abstinence.” Protracted abstinence in the rat spans a period after acute physical withdrawal has disappeared when elevations in ethanol intake over baseline and increased behavioral responsivity to stress persist (2-8 weeks post-withdrawal from chronic ethanol). The persistent increase in drug self-administration during protracted abstinence has been hypothesized to involve an allostatic-like adjustment such that the set point for drug reward is elevated (hedonic tolerance) [42]. These characteristics of drug addiction imply more than simply homeostatic dysregulation of hedonic function and executive function, but rather a dynamic break with homeostasis of these systems that has been termed allostasis.

Allostasis, originally conceptualized to explain persistent morbidity of arousal and autonomic function, is defined as “stability through change” [86]. Allostasis involves a feed-forward mechanism rather than the negative feedback mechanisms of homeostasis, with continuous re-evaluation of need and continuous readjustment of all parameters toward new set points. Thus, the very physiological mechanism that allows rapid responses to environmental challenges becomes the engine of pathology if adequate time or resources are not available to shut off the response (e.g., the interaction between CRF, norepinephrine, and dynorphin in the basal forebrain that could lead to pathological anxiety and dysphoria) [33]. Allostatic mechanisms also have been hypothesized to be involved in maintaining a functioning brain emotional system that has relevance for the pathology of addiction [42]. Two components that are hypothesized to account for the negative emotional state associated with addiction are decreased function of brain reward transmitters and circuits and recruitment of the brain antireward or stress systems (Figure 3). Repeated challenges, such is the case with drugs of abuse, lead to attempts of the brain via molecular, cellular, and neurocircuitry changes to maintain stability but at a cost. The cost is a worsening of the negative emotional state during acute and protracted withdrawal and fits the definition of allostatic load [54]. For the drug addiction framework elaborated here, the residual negative emotional state is considered an allostatic state [42]. An intriguing hypothesis to be elaborated below is that the same emotional systems engaged for the “fight or flight” response may also participate in consolidation of addiction-related memories.

Addiction, Antireward, and Emotional Memory

Much evidence indicates that drugs, and more specifically psychostimulant drugs, can enhance cognitive performance. Such effects may include actions on perception, attention, arousal, and motivation, as well as on learning and memory. However, possibly more important for the neurobiology of addiction, drugs of abuse may alter the memory of the positive and negative reinforcing effects of drug actions. Even more intriguing is whether the memory of drug actions has any unique neural substrate that conveys a particular additional salience to such memories. The hypothesis to be considered here is that the neural substrates for the dark side of addiction overlap signficantly with the neural substrates of “emotional” memory.

Much evidence from both human and animal studies supports the hypothesis that drugs of abuse can convey conditioned positive reinforcing properties and conditioned negative reinforcing properties. Animal models of drug craving and relapse continue to be developed and refined, but to date have largely reflected secondary sources of reinforcement such as conditioned reinforcement [52, 87]. A conditioned reinforcer can be defined as any neutral stimulus that acquires reinforcing properties through associations with a primary reinforcer. In a conditioned reinforcement paradigm involving drug self-administration, subjects are trained in an operant box containing two levers in which responses on one lever result in presentation of a brief stimulus followed by a drug injection (active lever), and responses on the other lever have no consequences throughout the experiment (inactive lever; [12, 82]). Subsequently, the ability of the previously neutral, drug-paired stimulus to maintain responding in the absence of drug injections provides a measure of the reinforcing value of the stimulus. Second-order schedules of reinforcement can also be used as a measure of the conditioned reinforcing properties of drugs [22]. Work in primates and rats suggests that reliable responding for cocaine can be established with a second-order schedule [79]. Noncontingent drug administration or previously neutral stimuli paired with drug delivery can also can elicit drug seeking following extinction (reinstatement). Drugs or cues that have been paired with drug self-administration or predict drug self-administration can serve as discriminative stimuli when applied noncontingently after extinction and will induce reinstatement of drug seeking behavior [13, 82, 88]. The conditioned place preference paradigm also provides a measure of conditioned reinforcement, which is conceptually similar to the measures provided by the operant paradigms. Several extensive reviews have been written on the place preference paradigm [10, 89, 90, 94].

The neural substrates for such conditioned positive reinforcing effects of drugs of abuse, particularly the neural substrates of reinstatement, involve activation of glutamatergic pathways from the frontal cortex to the nucleus accumbens and from the basolateral amygdala to the central nucleus of the amygdala and nucleus accumbens (for reviews, see [17, 30, 83].

Conditioned opiate withdrawal has been observed clinically. Former opioid addicts often report symptoms similar to opioid abstinence when returning to environments associated with drug experiences [62]. In an experimental study of former heroin addicts maintained on methadone, opioid antagonist injections were repeatedly paired with a tone and peppermint smell [63]. Subsequent presentation of only the tone and odor elicited both the subjective effects of discomfort as well as the objective physical signs of withdrawal. Similar effects have been observed in both primate and rodent models. Primates and rodents that were allowed to self-administer opioids intravenously 23-24 h per day were challenged with an opioid antagonist and a previously neutral stimulus. The opioid antagonist elicited a compensatory-like increase in responding for the opioid. After repeated pairings, presentation of the conditioned stimulus alone resulted in a conditioned increase in responding for the opioid, similar to what was observed with the opioid antagonist alone [23, 31]. The conditioned negative reinforcing effects of drugs of abuse have only been studied in the context of opioid drugs in animal models but involve the basolateral amygdala [80] and possibly associative mechanisms similar to the conditioned positive reinforcing properties of drugs of abuse. However, an emotional component to conditioned withdrawal may also recruit the brain stress circuitry implicated in the negative reinforcing properties of drug withdrawal and protracted abstinence. Indeed this “emotional memory” may contribute to the allostatic state hypothesized to perpetuate protracted withdrawal.

The neural substrates for emotional memory have been explored extensively and overlap with some of the neural substrates for conditioned positive and negative reinforcement associated with drugs of abuse. The neural substrates for emotional memory also form an intriguing neuropharmacological parallel with the neural substrates associated with the negative emotional states associated with abstinence in drug dependence. Emotional experiences are often associated with lasting and vivid memories that have also been described as “flashbulb memories” [11]. A key brain region that mediates the consolidation of such emotional memories is the basolateral amygdala and the convergence of stress hormones and other neuromodulatory noradrenergic systems systems contained therein [55, 56]. In a series of elegant studies by McGaugh, Roosendal, and colleagues, the basolateral amygdala was shown to mediate the memory-modulating effects of adrenal stress hormones, with a key role for noradrenergic activation. The basolateral system modulates consolidation of many different kinds of information. In human studies, the degree of activation of the amgydala by emotional arousal correlates highly with subsequent recall [9]. Additionally, as noted above, the basolateral amygdala has a key role in mediating conditioned positive and conditioned negative reinforcement associated with drugs of abuse.

The role of noradrenergic mechanisms in enhancing memory consolidation was established in a series of studies with injections of noradrenergic agonists and antagonists into the basolateral amygdala. Norepinephrine or noradrenergic agonists injected directly into the basolateral amygdala immediately post-training facilitated the memory of emotionally arousing training tasks such as inhibitory avoidance [18], contextual fear conditioning [49], a water maze spatial task [26], and an object recognition task [74]. Post-training injections of β-noradrenergic antagonists had the opposite effect of impairing consolidation of memory of emotionally arousing tasks [20, 26, 59]. Adrenal hormones also facilitated consolidation of emotionally arousing tasks via interactions with noradrenergic mechanisms in the basolateral amygdala [75]. Particularly germane to the present thesis, activation of CRF in the basolateral amygdala via inhibition of the CRF-binding protein produced noradrenergic-dependent facilitation of memory consolidation [76]. These results suggest that CRF may play a selective role in consolidation of long-lasting memories of emotionally arousing experiences [76].

The integration of brain stress systems at two levels of the amygdala may provide a compelling basis for an overwhelming drive to seek drugs in dependent individuals. The basolateral amygdala has a major projection to the central nucleus of the amygala. Classically, in fear conditioning, associative processes have been localized to the basolateral amygdala, and the expression of fear has been localized to the output of the amygdala: the central nucleus of the amygdala. Thus, activation of CRF and norepinephrine systems in both the central nucleus of the amygdala and basolateral amygdala may influence two separate domains that may combine to potentiate each domain: the negative emotional state of acute withdrawal and protracted abstinence and the consolidation of memories of emotionally arousing experiences (Figure 4). For example, the central nucleus of the amygdala is well documented to output to brain regions implicated in emotional expression, such as the hypothalamus and brain stem. Conversely, the basolateral amygdala is hypothesized to mediate consolidation of memories of emotionally arousing experiences via the nucleus accumbens, caudate nucleus, hippocampus, and entorhinal cortex [56]. In fear conditioning, two competing models of information processing within the amygdala have been hypothesized to be engaged during learning. In the serial model, information about the conditioned stimulus and unconditioned stimulus enters and is associated with the BLA, and this information is then transmitted to the central nucleus of the amygdala for the fear expression. Alternatively, a parallel model proposes that the basolateral amygdala and central nucleus of the amygdala both perform associative functions [98]. Thus, hormonal, noradrenergic, and CRF systems may be hypothesized to be activated by the aversive consequences of drug withdrawal to form the basis for negative reinforcement that drives drug seeking and potentiate associative mechanisms that perpetuate the emotional state that helps drive the allostatic state of addiction.

Figure 4 
Schematic diagram summarizing the hypothesized relationship between motivational dependence and emotional memory. Emotional states are well known to trigger relapse, and a mechanism may be a parallel action in which the negative emotional state of drug ...

Acknowledgments

The author would like to thank Michael Arends for his assistance with the preparation of this manuscript. Research was supported by National Institutes of Health grants AA06420 and AA08459 from the National Institute on Alcohol Abuse and Alcoholism, DA10072, DA04043, and DA04398 from the National Institute on Drug Abuse, and DK26741 from the National Institute of Diabetes and Digestive and Kidney Diseases. Research was also supported by the Pearson Center for Alcoholism and Addiction Research. This is publication number 19965 from The Scripps Research Institute.

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Long-term loss of dopamine release mediated by CRF-1 receptors in the rat lateral septum after repeated cocaine administration. (2013)

Behav Brain Res. 2013 May 16. pii: S0166-4328(13)00283-0. doi: 10.1016/j.bbr.2013.05.012. [Epub ahead of print]

Sotomayor-Zárate R, Renard GM, Araya KA, Carreño P, Fuentealba JA, Andrés ME, Gysling K.

Source

Millennium Science Nucleus in Stress and Addiction, Department of Cell and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile; Centro de Neurobiología y Plasticidad Cerebral, Departamento de Fisiología, Facultad de Ciencias, Universidad de Valparaíso.

Abstract

The lateral septum (LS) is a brain nucleus associated to stress and drug addiction. Here we show that dopamine extracellular levels in the lateral septum are under the control of corticotrophin releasing factor (CRF). Reverse dialysis of 1μM stressin-1, a type 1 CRF receptor (CRF-R1) agonist, induced a significant increase of LS dopamine extracellular levels in saline-treated rats that was blocked by the co-perfusion of stressin-1 with CP-154526, a specific CRF-R1 antagonist. Repeated cocaine administration (15mg/kg; twice daily for 14 days) suppressed the increase in LS dopamine extracellular levels induced by CRF-R1 activation. This suppression was observed 24hours, as well as 21 days after withdrawal from repeated cocaine administration.

In addition, depolarization-induced dopamine release in the LS was significantly higher in cocaine- compared to saline-treated rats. Thus, our results show that the activation of CRF-R1 in the LS induces a significant increase in dopamine extracellular levels. Interestingly, repeated cocaine administration induces a long-term suppression of the CRF-R1 mediated dopamine release and a transient increase in dopamine releasability in the LS.

Making a bad thing worse: adverse effects of stress on drug addiction (2008)

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Abstract

Sustained exposure to various psychological stressors can exacerbate neuropsychiatric disorders, including drug addiction. Addiction is a chronic brain disease in which individuals cannot control their need for drugs, despite negative health and social consequences. The brains of addicted individuals are altered and respond very differently to stress than those of individuals who are not addicted. In this Review, we highlight some of the common effects of stress and drugs of abuse throughout the addiction cycle. We also discuss both animal and human studies that suggest treating the stress-related aspects of drug addiction is likely to be an important contributing factor to a long-lasting recovery from this disorder.

Introduction

Drug abuse is among the top 3 health problems in the United States in terms of economic and health care costs. The compulsive use of drugs despite serious negative consequences defines addiction as a mental illness (1). To date, however, there are very few effective medications to treat this disease. Addiction is not characterized as a single incident, but rather by a series of events initiated by the acute rewarding effects of drugs followed by a transition into chronic drug use (Figure ​(Figure1).1). Many addicts experience periods of abstinence, but frequently relapse to chronic drug taking. The cyclical nature of chronic drug use, involving periods of drug abstinence and subsequent relapse, highlights the presence of this disease throughout the lifetime of an individual. Animal research and human imaging studies have identified the brain circuitry mediating the initial rewarding properties of drugs (1); however, the molecular and cellular mechanisms responsible for the development and persistence of the addicted state remain elusive. Although many factors can contribute to initial and continued drug use, exposure to either psychological or physiological stress at any point in the addiction cycle seems to worsen this disease, augmenting all drug-seeking behaviors, including initial drug taking, drug craving, and relapse (2, 3). This Review details the integration of stress and addiction circuitry and discusses the molecular and cellular changes common to both following exposure to stress or drugs of abuse. In addition, current therapies used to treat addiction, in particular stress-induced relapse, are discussed.

Figure 1 
The cycle of addiction.

Brain circuitry, stress, and addiction

Mesolimbic dopamine pathway.

All drugs of abuse exert their primary rewarding effects on the mesolimbic dopamine reward pathway, which consists of dopamine neurons originating in the ventral tegmental area (VTA) and extending to the nucleus accumbens (NAc) and the prefrontal cortex (PFC) (Figure ​(Figure2)2) (4). Psychomotor stimulants, such as cocaine, amphetamine, opiates, nicotine, and alcohol, in addition to natural rewards, such as sex and food, cause a release of dopamine in the NAc regardless of their mechanism of action (5). Several lines of evidence indicate that the mesolimbic dopamine reward pathway is also responsive to stress. First, in animal models, acute exposure to a stressor, such as footshock (6) and tail pinch (7), produces an increase in dopamine release in the NAc. Second, exposure to either drugs of abuse or stress produces similar alterations in the electrophysiology of neurons in the mesolimbic dopamine reward pathway in animals. Enhanced excitatory synaptic transmission, as evidenced by an increase in glutamate receptor activation, occurs in VTA dopamine neurons following exposure to either stress or any one of several drugs of abuse, including cocaine, nicotine, and alcohol (8). Finally, both stress and drugs of abuse cause alterations in specialized extensions of neurons called dendrites (911). Rats subjected to chronic restraint stress exhibit decreases in dendritic branching in the medial PFC (11). Alterations in dendritic branching are also observed following exposure to addictive drugs, with an increase occurring following exposure to cocaine and amphetamine, whereas reductions in branching occur following exposure to morphine (9, 10). Together, these findings indicate that stress and drugs of abuse act similarly to affect the neurochemistry, electrophysiology, and morphology of neurons involved in reward pathways.

Figure 2 
Reward and stress pathways in the brain.

Molecular changes associated with stress exposure and drug addiction are also similar. Because of the long-lasting nature of addiction, changes in gene expression might be necessary for the development and persistence of this disease. Proteins well situated to effect these long-term changes are regulators of gene transcription. A large body of evidence demonstrates that a member of the leucine zipper family of transcription factors, FosB (in particular, a truncated form of this protein, ΔFosB), accumulates in the NAc following chronic administration of drugs of abuse in rodents (12). Similarly, chronic stress increases ΔFosB levels in the NAc as well as in the frontal cortex and basolateral amygdala (13). Another member of this same class of transcription factors, cAMP response element–binding protein (CREB), can also function at the intersection of drug reward and stress response. CREB is regulated by both acute and chronic drug treatment throughout brain reward areas (14, 15). Various stressors, including shock, repeated immobilization, and forced swim, activate the hypothalamic-pituitary-adrenal (HPA) axis and are associated with increased phosphorylation of CREB in several regions of the brain (16), including the NAc (17). In addition, a CREB-related transcription factor, inducible cAMP element repressor, demonstrates parallel mRNA changes in the NAc following either amphetamine administration or exposure to a stressor (18). Thus, stress and addictive drugs might act through common molecular mechanisms within similar brain circuits to perpetuate the addiction cycle. However, additional research is necessary to determine whether drugs and stress regulate similar target genes downstream of these transcriptional regulators.

The HPA axis.

Most physiological stressors exert their effects on the HPA axis, the primary endocrine stress pathway. Corticosterone-releasing factor (CRF) is secreted from a subregion of the hypothalamus known as the paraventricular nucleus of the hypothalamus (PVN) to stimulate the output of adrenocorticotropin hormone (ACTH). Following its release from the anterior pituitary, ACTH subsequently stimulates the secretion of adrenal glucocorticoids — cortisol in humans and corticosterone in animals — into the bloodstream (Figure ​(Figure2).2). Dysfunction of this peripheral stress circuit contributes to various stress-related neuropsychiatric diseases, including addiction (19).

Similar to the mesolimbic dopamine pathway, the HPA axis is activated in rodents and nonhuman primates following acute administration of many addictive substances — including cocaine, amphetamine, ethanol, opiates, and nicotine — and causes increased ACTH and corticosterone levels in plasma (20). Chronic administration of drugs of abuse in the same animal models results in either a sustained increase in HPA axis function, in the case of cocaine and amphetamine, or a reduced effect of the initial activating effects of the drug, in the case of morphine, nicotine, and alcohol (2124). Human studies demonstrate similar perturbations following illicit drug use, with slight differences. As in animal models, acute administration of cocaine (25), alcohol (26), and nicotine (27) increases cortisol levels, whereas acute exposure to opiates decreases cortisol levels (28, 29). Activation of the HPA axis is maintained in cocaine addicts (30), whereas following chronic opiate use, HPA responses are reduced over time (31), a more typical response to repeated exposure to a stressor (32, 33). However, it is unclear whether the irregularities observed in the HPA axis following drug administration indicate a vulnerability to addiction or are the result of prolonged drug exposure.

Extrahypothalamic CRF.

In addition to activating the HPA axis, CRF can mediate neurotransmission within the CNS. The placement of CRF and its receptors, CRF receptor 1 (CRFR1) and CRFR2, throughout the limbic system and neocortex suggests a critical role for this peptide in affective disorders, including depression, anxiety, and, more recently, addiction (34). CRF expression is modulated by both acute and chronic drug administration (34) as well as by withdrawal from the addictive drug. Cocaine, morphine, and alcohol tend to increase CRF expression acutely; however, the direction in which CRF expression is altered chronically and following withdrawal from these various drugs depends on both the brain region and drug studied (ref. 34 and Table ​Table1).1). Although smokers often report stress relief as a motivating factor for continued tobacco use, very little information is available detailing the effect of nicotine on these CRF circuits, in particular the effects of both acute and chronic nicotine administration. During nicotine withdrawal, increased activation of CRF-containing cells in the PVN is observed (35), and increased levels of CRF are reported following withdrawal in rats allowed to self administer nicotine (36). The differences in CRF expression between drug classes highlight the distinctive pharmacological and molecular mechanisms throughout the CNS that each drug uses in exerting its addictive properties. Furthermore, the alterations in CRF protein and mRNA observed during the withdrawal period suggest that drug administration causes transcriptional and translational modifications long after the last drug exposure.

Table 1  
Alterations in mRNA and protein levels of CRF throughout the addiction cycle following exposure to cocaine, morphine, or alcohol

Additional brain circuits.

Although this Review is focused on the role of stress circuits in the addiction process, it should be noted that these pathways are not isolated in their activity. The central CRF system, the peripheral HPA stress circuits, and the mesolimbic reward pathway are all continuously activated or repressed by complex interactions with other pathways, including the endogenous opioid and noradrenergic systems (37, 38), both of which are important in mediating stress and drug responses. Furthermore, many brain areas throughout the CNS are altered functionally upon exposure to drugs of abuse. Therefore, the interconnectivity throughout the brain needs to be more fully addressed as we continue to determine the molecular mechanisms underlying addiction and the role that stress plays in this process.

Effect of stress on the addiction cycle

Individuals with stress-related psychiatric disorders, such as anxiety and depression, often engage in some form of drug use. Furthermore, exposure to chronic stressful life events, such as physical or sexual abuse (39), is linked to an increase in nicotine, alcohol, and cocaine usage (40). Recently, a study demonstrated that the greater the physical abuse in childhood (i.e., the longer it lasted), the more likely the subject was to develop drug addiction later in life (41). In addition, stress exposure can increase current drug use and precipitate relapse back to drug-taking behaviors (2, 3). Although chronic stress can produce changes in weight loss as well autonomic and endocrine outputs, the significance of these alterations on vulnerability to addiction behaviors has not been systematically characterized. However, the correlative observations in humans that stress exposure can affect various stages of the addiction cycle are supported by evidence from animal studies. Furthermore, these animal studies have enhanced our ability to investigate the underlying mechanisms and molecular targets that are involved in the interaction between stress and addiction.

Acquisition of drug taking.

Acquisition is defined as the initial, rewarding exposure to a drug of abuse with development into more chronic use. It has long been hypothesized that exposure to a stressful event or situation would increase the rate of acquisition to drug taking. In animal models, exposure to physiological as well as physical stressors, including social isolation, tail pinch, and footshock, can enhance initial amphetamine and cocaine self administration (4244). Furthermore, repeated exposure to forced swim stress can augment the rewarding properties of cocaine (45). These studies implicate stress in modulating the initial rewarding effects of addictive drugs.

Corticosterone release via the HPA axis is vital to the acquisition of drug administration. Inhibiting corticosterone release by adrenalectomy or pharmacologic treatment blocks cocaine self administration in rats (46, 47). Furthermore, corticosterone release following drug administration in rats increases neuronal activity above the critical levels needed for self administration to occur (48). This additional neuronal activation by the HPA axis is particularly evident at lower doses of cocaine, such that doses not normally rewarding are now readily self administered. These results are consistent with a study that examined corticosterone levels in rats that exhibit different behavioral and endocrine responses to a novel environment (49). Rats that showed increased locomotor activity and high corticosterone levels upon exposure to a novel environment were termed high responders, whereas low responders exhibited decreased locomotor activity and lower corticosterone levels. Following this initial classification, animals were trained to self-administer cocaine. Low responders did not learn to self administer cocaine, whereas robust self administration was observed in rats assessed as high responders. Interestingly, daily corticosterone administration induced and maintained amphetamine self administration in the low-responding rats, effectively switching their behavior to that of high responders (49).

The ability of corticosterone to modulate cocaine reward can be mediated by glucocorticoid receptors (GRs) located on neurons throughout the mesolimbic dopamine reward pathway (50). Adrenalectomized animals exhibit a blunted dopamine response in the NAc following either drug exposure (51) or stress (7). Corticosterone replacement prevents the attenuation of this dopamine response. Furthermore, GR antagonists decrease extracellular dopamine levels in the NAc by 50% (52), similar to the decrease observed following an adrenalectomy (51). In addition, GR antagonists locally injected into the VTA decrease morphine-induced increases in locomotor activity (52), indicating that activation of GRs in the VTA can mediate dopamine-dependent behavioral outputs. Interestingly, in mice where the gene encoding the GR was deleted specifically in the CNS, a dose-dependent decrease in motivation to self administer cocaine was observed (53). These results suggest that the dopamine increase observed in rodents following either drug administration (51) or stress (7) is dependent, at least in part, on the release of corticosterone from the HPA axis and the subsequent activation of GR.

The role of CRF in the acquisition of drug reward has not been thoroughly investigated. CRF protein and mRNA levels are altered following acute administration of many addictive drugs (34). Studies using CRFR1 antagonists demonstrate their involvement in the initial behavioral and biochemical effects of cocaine. For example, pharmacological blockade of CRFR1 inhibits cocaine-induced dopamine release (54) as well as reductions in the rewarding properties of cocaine (54) and locomotor activating effects (54, 55). These studies point to a role of CRF in modulating the initial effects of addictive drugs, but more studies are needed to fully determine the role of CRF in the development of drug addiction.

Withdrawal.

Abnormalities in stress circuitry continue following the cessation of drug taking, in both immediate and long-term withdrawal. Activation of the HPA axis, as evidenced by a marked increase in corticosterone levels, occurs following acute withdrawal from most drugs of abuse both in humans and in animal models (20). Interestingly, following this initial activation, basal corticosterone and cortisol levels return to normal in humans and rodents, respectively (20). However, during long-term withdrawal from psychostimulants and opiates, the HPA axis displays an augmented response upon exposure to a stressor. In former cocaine (56) and opiate addicts (57), increased levels of ACTH and cortisol were measured following administration of the chemical stressor metyrapone. Metyrapone blocks the synthesis of cortisol, disrupting the normal negative feedback of cortisol on the hypothalamus and thereby causing activation of the HPA stress pathway (20). Furthermore, in abstinent cocaine users, hyperresponsiveness to emotional and physical stress, as well an increased drug craving, is observed (58), which is consistent with an altered HPA axis. In rats, during acute withdrawal, corticosterone responses are augmented upon exposure to restraint stress (59). These data suggest that the stress response can be sensitized by drug exposure and subsequent withdrawal. In contrast, recent evidence has demonstrated an attenuated response to stress during nicotine withdrawal in animals. Corticosterone levels were substantially lower in rats exposed to restraint stress during nicotine withdrawal, although their basal corticosterone levels were similar (60). Chronic smokers demonstrate increased cortisol secretion (61, 62), and a reduction in cortisol after smoking cessation has been associated with increased withdrawal severity and relapse (63, 64). Together, these studies demonstrate alterations in the responsiveness of the HPA axis to a stressor during long-term withdrawal, which might play a role in the ability of stressors to reinstate drug seeking well after the drug is removed.

Alterations in CRF peptide and mRNA levels throughout the CNS are observed following acute withdrawal from several drugs of abuse, including cocaine and opiates, and these alterations vary by brain region as well as the drug administered. Interestingly, increases in CRF mRNA in the PVN correlate with increases in anxiety behaviors during ethanol, cocaine, and morphine withdrawal (6567). In addition, blockade of the CRF system with antagonists or antibodies decreases the anxiety observed in this acute withdrawal phase (6567). CRFR1 antagonists decreased the physical symptoms of morphine withdrawal in dependent rats (67). Together, these data suggest that the CRF system plays a role in the psychological as well as the physical symptoms of acute withdrawal from addictive drugs. However, the role of CRF or stress circuitry in long-term withdrawal has yet to be elucidated.

Reinstatement of drug seeking.

Many theories of addiction hypothesize that stress is one of the primary causes of relapse in human addicts (2, 3). Using animal models, several laboratories have demonstrated that exposure to an acute stressor can effectively reinstate drug seeking of various drugs, including opiates, psychostimulants, alcohol, and nicotine (6871). Stress facilitates relapse by activating central CRF brain circuits. Animals that have been trained to self administer drug and then have the drug removed reinitiate lever pressing following an intracerebroventricular CRF injection (72). A distinct circuitry involving CRF in the extended amygdala, an important structure for emotional and effective behavior, has been delineated in mediating stress-induced relapse. Structures comprising the extended amygdala overlap with those of the reward pathway, including the central nucleus of the amygdala, bed nucleus of the stria terminalis (BNST), and parts of the NAc (Figure ​(Figure2)2) (73). The significance of this pathway in the addiction cycle is evident primarily in relapse or reinstatement. Inactivation of the CRF projection from the central amygdala to the BNST blocks stress-induced (e.g., by footshock) cocaine reinstatement (74, 75), and local injections of D-Phe, a nonspecific CRF receptor antagonist, into the BNST, but not the amygdala, attenuates footshock-induced reinstatement (75). Specifically, CRFR1s localized in the BNST, but not the amygdala or NAc, mediate stress-induced relapse into drug seeking (68). Interestingly, selective CRFR1 antagonists attenuate footshock-induced reinstatement of cocaine or opiate seeking (68, 76) but have no effect on drug-induced reinstatement (72, 77). These data demonstrate that stress stimulation of the CRF-containing pathway, originating in the amygdala and extending into the BNST, and subsequent activation of CRFR1 localized in the BNST, triggers drug seeking in previously addicted animals.

Recently, CRF has been detected in the VTA, the site of origin of the dopamine neurons of the reward pathway (78). In both cocaine-naive and cocaine-experienced rats, CRF is released into the VTA following an acute footshock; however, the source of this CRF is not known (78). In cocaine-experienced animals, glutamate and dopamine are released in the VTA in conjunction with CRF in response to a stressor. This release of glutamate and dopamine is dependent upon CRF and subsequent activation of its receptors, as local injections of CRF antagonists into the VTA attenuated the release of these 2 neurotransmitters (78, 79). In addition, administration of CRFR2 antagonists, but not CRFR1 antagonists, locally into the VTA blocked the ability of footshock to reinstate cocaine seeking in a self-administration paradigm (79). Taken together, these studies suggest a role for CRF in modulating dopamine cell activity, specifically following drug experience.

Although studies have clearly demonstrated a role for CRF in reinstatement of stress-induced drug seeking, very few have examined whether other molecular mechanisms are important in stress-induced reinstatement. The transcription factor CREB, implicated in both stress and addiction, was recently shown to be involved in stress-induced reinstatement. CREB-deficient mice do not exhibit stress-induced reinstatement of cocaine-conditioned place preference (70). However, these mice do exhibit reinstatement of drug seeking to a priming dose of cocaine (70). This deficit in stress- and not drug-induced reinstatement indicates a specific requirement for CREB in stress-induced behavioral responses to drugs of abuse. Of interest, a putative CREB target gene, brain-derived neurotrophic factor (BDNF), localized in the VTA and the NAc of the mesolimbic dopamine reward pathway, was increased following withdrawal from chronic cocaine (80). The increase in BDNF in these brain areas positively correlated with the response of the rats to drug-associated cues (80), and more recent studies demonstrate that BDNF might facilitate relapse to drug-seeking behavior (81). Additional experiments detailing the molecular mechanisms of stress-induced reinstatement are needed to fully understand this complex process.

Therapies

Both animal and human studies have clearly demonstrated a role for stress throughout the addiction process. Addicts describe stress as one of the key reasons for continuing drug use or relapsing back into drug taking following a period of abstinence. Therefore, minimizing the effect of stress throughout the addiction cycle, particularly during the withdrawal period, is essential in the treatment of addiction. However, current treatments for addiction are inadequate, as about half of all addicts relapse back into drug taking. Despite the high levels of relapse, several classes of drug therapies are showing promise in treating some aspects of addiction. Although some of these treatments target the stress and addiction circuits, such as the extrahypothalamic CRF circuits discussed above, others have taken a novel approach in their treatment mechanisms, targeting secondary systems that might modulate stress and addiction pathways.

CRFR1 antagonists.

As animal models have clearly demonstrated, CRFR1 antagonists are effective in attenuating stress-induced relapse to drug taking (76, 8284). CP-154,526, a CRFR1 nonpeptide antagonist, attenuates stress-induced relapse to drug seeking in rats (77). Antalarmin, MJL-1-109-2, and R121919, all CRFR1 nonpeptide antagonists, decrease ethanol self administration in ethanol-dependent rats, with no effect on ethanol intake in nondependent rats (85). Furthermore, antalarmin has been shown to decrease ACTH and corticosterone levels in nonhuman primates in addition to decreasing behavioral anxiety scores (86). Together these data suggest that CRFR1 might be an effective therapeutic target for medications to treat drug addiction. However, in the human population, progress toward applying compounds that target this receptor to the treatment of addiction has been slow. Currently, antalarmin is in phase I and phase II clinical trials for the treatment of anxiety and depression, although no results from these studies have been made public (87). In addition, R121919 has been shown in an open-label clinical trial to be effective in reducing depression and anxiety-like symptoms in humans (88, 89), and more recently, the high-affinity CRFR1 antagonist NB1-34041 has demonstrated efficacy in attenuating an elevated stress response both in animals and in humans, but no studies have evaluated the therapeutic value of these compounds in treating the drug-addicted population (90).

Varenicline.

Nicotine is believed to be the primary factor responsible for the addictive properties of tobacco use. Nicotine acts on α4β2 receptors, which are involved in the rewarding aspects of this drug, specifically through the release of dopamine in the NAc (91). Therefore, a partial agonist of this receptor, by blocking the binding of the receptor, might ease withdrawal symptoms. Varenicline, an α4β2 acetylcholine nicotinic receptor partial agonist, has shown promise in nicotine addiction. As reported in several clinical trials, the rates of continuous abstinence from smoking are higher in those patients given varenicline compared with placebo (92, 93). Reduced craving and withdrawal symptoms were also observed (92, 94). In animal studies, varenicline reduces nicotine self administration (95), and more recently, rats showed decreased ethanol consumption following acute and chronic varenicline administration (96). As these studies show, varenicline is an effective treatment option for smoking cessation. However, no studies have specifically examined this drug during reinstatement in animal models.

Antidepressants.

Based on the potential role of CRFR1 antagonists in treating depression, and given that stress can precipitate both depression and addiction, other antidepressant medications have been evaluated over the years for efficacy in treating drug abuse. Bupropion, an atypical antidepressant, has shown significant promise in the treatment of nicotine dependence (97). Bupropion’s efficacy in smoking cessation was observed anecdotally by a clinician treating patients for depression (98). Since this keen observation, bupropion has been shown to be effective in numerous clinical trials as a smoking cessation agent, in particular in combination with nicotine replacement therapy (98). Bupropion acts at norepinephrine and dopamine transporters, inhibiting reuptake of these neurotransmitters. In addition, it functions as an antagonist at α4β2 nicotinic receptors (99). Recently, a study using a rodent model of nicotine dependence demonstrated decreases in physical signs associated with nicotine withdrawal following bupropion administration (100).

Of the classical antidepressants, only desipramine (DMI), a tricyclic antidepressant, has shown promise in treating cocaine addiction. Past studies have reported decreases in cocaine intake in self-administering rats (101) and decreases in cocaine craving in humans following chronic DMI treatment (102). However, a recent study in crack cocaine addicts demonstrated little to no efficacy of DMI treatment (103). Currently, DMI is rarely used to treat cocaine addiction because other medications, such as modafinil, are showing more promise in clinical trials (98). The exact mechanism of action of modafinil is not known, although it has been shown to inhibit the reuptake of dopamine and norepinephrine as well as to activate glutamate and inhibit GABA neurotransmission (104). Of interest, other compounds that target the GABA system, in particular those that increase GABA activation, have been shown to be effective in treating cocaine craving and relapse (98).

Lofexidine.

The noradrenergic system has been implicated in stress-induced reinstatement of drug seeking. Lofexidine, an α2 adrenergic receptor agonist, reduces opioid withdrawal symptoms by decreasing noradrenergic outflow in the CNS (105). Animal models have demonstrated that lofexidine attenuates footshock-induced reinstatement of drug seeking (106), as administration of α2 adrenergic receptor agonists or selectively lesioning noradrenergic projections to forebrain areas effectively blocks stress-induced reinstatement in rats (106, 107). Furthermore, local injections of noradrenergic antagonists into the BNST and central amygdala inhibited the ability of footshock to reinstate drug seeking (108). In addition, a recent human study showed that a combination of lofexidine and naltrexone, a μ opioid antagonist, substantially increased abstinence rates in current opiate users as well as decreasing stress-induced drug craving when compared with naltrexone alone (109). Although lofexidine is approved for use in opioid withdrawal in the United Kingdom, more studies are needed to determine fully the role for lofexidine in stress-induced opiate relapse.

Additional medications.

Several other medications have been approved for substance abuse, specifically for the treatment of alcoholism. Naltrexone decreases baseline drinking levels as well as alcohol craving and overall number of relapse episodes back into alcohol consumption (110). However, naltrexone is not effective in blocking stress-induced reinstatement in animal models (111), nor has it been effective in treating stress-induced drug craving in humans (112). Acamprosate, a modulator of the N-methyl-D-aspartic acid receptor, is also approved to treat alcohol dependence. Used to prevent relapse back into alcoholism, it has been shown to reduce alcohol intake as well as craving (113). In addition, acamprosate alleviates anxiety associated with alcohol withdrawal and increases alcohol abstinence (98). However, little is know regarding the ability of acamprosate to block stress-induced relapse.

Conclusion

As has been hypothesized in humans, and now demonstrated convincingly in animal studies, stress is one of the key factors in facilitating reward associated with initial drug exposure. In addition, stress increases drug craving and relapse back into drug seeking. Studies have demonstrated a positive correlation of stress and drug craving in humans (114), indicating an activation of reward pathways following exposure to a stressor (115). A significant gap in our understanding of addiction is whether alterations in brain chemistry observed in chronic addicts is caused by environmental factors, such as physical or sexual abuse, which are known to lead to illicit drug use, or by the long-term drug use itself. Recently, it was demonstrated that humans with self-reported increased life stress display increased drug reward to an acute injection of amphetamine (116), further supporting the hypothesis that exposure to a chronic stress environment increases the risk of developing addictive behavior. Furthermore, the high-stress group exhibited a decrease in dopamine release at baseline as well as in response to amphetamine (116), indicating that this decreased dopamine response might constitute a vulnerability to addiction. In a monkey model of social hierarchy, the amount or availability of dopamine D2 receptors was increased in dominant monkeys, whereas no change was observed in subordinate cage mates (117). Interestingly, cocaine was more reinforcing in the subordinate than in the dominant monkeys (117), indicating that environmental modifications of the dopamine system may alter vulnerability to addiction. However, future studies examining the molecular targets and signaling pathways altered by chronic environmental, physical, and psychological stress and their effects on addictive behaviors need to be completed.

Although effective treatments for drug abuse involve both behavioral therapy and medication, the list of medications approved by the FDA for treatment of addiction is limited. Indeed, there are currently no approved medications for cocaine addiction. Furthermore, many of the treatments available are given when the addict is actively using the addictive substance. Current treatments for alcohol, nicotine, and opiate addiction are used to reduce or stop drug intake. For example, naltrexone decreases alcohol intake, allowing for a more productive lifestyle. Bupropion is prescribed in conjunction with nicotine replacement therapy when patients are still smoking. Very few treatments are prescribed during the withdrawal period, in particular to prevent relapse. Over the last 10–15 years, research into the effects of stress on the addiction cycle has identified both peripheral and central CRF systems as key players in linking stress and addiction. Although therapeutic drugs targeting this system are being examined for their treatment efficacy, additional research examining withdrawal and relapse, in particular stress-induced relapse, is needed to further determine putative therapeutic targets.

Acknowledgments

The authors wish to thank Charles P. O’Brien for critically reading this manuscript. This work was supported by National Institute on Drug Abuse grant DA116-49-01A2 (to J.A. Blendy).

Footnotes

Nonstandard abbreviations used: ACTH, adrenocorticotropin hormone; BNST, bed nucleus of the stria terminalis; CREB, cAMP response element–binding protein; CRF, corticosterone-releasing factor; CRFR, CRF receptor; GR, glucocorticoid receptor; HPA, hypothalamic-pituitary-adrenal (axis); NAc, nucleus accumbens; PFC, prefrontal cortex; PVN, paraventricular nucleus of the hypothalamus; VTA, ventral tegmental area.

Conflict of interest: The authors have declared that no conflict of interest exists.

Citation for this article: J. Clin. Invest. 118:454–461 (2008). doi:10.1172/JCI33946.

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Neurobiological Substrates for the Dark Side of Compulsivity in Addiction (2009)

Neuropharmacology. Author manuscript; available in PMC Jan 1, 2010.

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Abstract

Drug addiction can be defined by a compulsion to seek and take drug, loss of control in limiting intake, and the emergence of a negative emotional state when access to the drug is prevented. Drug addiction impacts multiple motivational mechanisms and can be conceptualized as a disorder that progresses from impulsivity (positive reinforcement) to compulsivity (negative reinforcement). The construct of negative reinforcement is defined as drug taking that alleviates a negative emotional state. The negative emotional state that drives such negative reinforcement is hypothesized to derive from dysregulation of key neurochemical elements involved in reward and stress within the basal forebrain structures involving the ventral striatum and extended amygdala. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission, such as decreases in dopamine and opioid peptide function in the ventral striatum, but also recruitment of brain stress systems, such as corticotropin-releasing factor (CRF), in the extended amygdala. Acute withdrawal from all major drugs of abuse produces increases in reward thresholds, increases in anxiety-like responses, and increases in extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists also block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the compulsivity of addiction. Other components of brain stress systems in the extended amygdala that interact with CRF and may contribute to the negative motivational state of withdrawal include norepinephrine, dynorphin, and neuropeptide Y. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for a negative emotional state that is responsible for the negative reinforcement driving, at least in part, the compulsivity of addiction.

Keywords: addiction, opponent process, stress, extended amygdala, corticotropin-releasing factor

1. Definitions and conceptual framework for compulsivity in addiction

Drug addiction is a chronically relapsing disorder characterized by (i) compulsion to seek and take the drug, (ii) loss of control in limiting intake, and (iii) emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) reflecting a motivational withdrawal syndrome when access to the drug is prevented (defined here as dependence) (Koob and Le Moal, 1997). Addiction is assumed to be identical to the syndrome of Substance Dependence (as currently defined by the Diagnostic and Statistical Manual of Mental Disorders; American Psychiatric Association, 1994). Clinically and in animal models, the occasional but limited use of a drug with the potential for abuse or dependence is distinct from escalated drug intake and the emergence of a chronic drug-dependent state.

Drug addiction has been conceptualized as a disorder that involves elements of both impulsivity and compulsivity, where impulsivity can be defined behaviorally as “a predisposition toward rapid, unplanned reactions to internal and external stimuli without regard for the negative consequences of these reactions to themselves or others” (Moeller et al., 2001). Impulsivity is measured in two domains: the choice of a smaller, immediate reward over a larger, delayed reward (Rachlin and Green, 1972) or the inability to inhibit behavior by changing the course of action or to stop a response once it is initiated (Logan et al., 1997). Impulsivity is a core deficit in substance abuse disorders (Allen et al., 1998) and in neuropsychiatric disorders such as attention deficit hyperactivity disorder. Operationally, delay-to-gratification tasks (delayed discounting tasks) (impulsive choice) and the stop-signal or go/no-go task (behavioral impulsivity) have been used as measures of impulsivity (Fillmore and Rush, 2002; Green et al., 1994). Compulsivity can be defined as elements of behavior that result in perseveration in responding in the face of adverse consequences or perseveration in the face of incorrect responses in choice situations. These elements are analogous to the symptoms of Substance Dependence as outlined by the American Psychiatric Association: continued substance use despite knowledge of having had a persistent or recurrent physical or psychological problem and a great deal of time spent in activities necessary to obtain the substance (American Psychiatric Association, 2000).

Collapsing the cycles of impulsivity and compulsivity yields a composite addiction cycle comprised of three stages—preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect—where impulsivity often dominates at the early stages and compulsivity dominates at terminal stages. As an individual moves from impulsivity to compulsivity, a shift occurs from positive reinforcement driving the motivated behavior to negative reinforcement driving the motivated behavior (Koob, 2004). Negative reinforcement can be defined as the process by which removal of an aversive stimulus (e.g., negative emotional state of drug withdrawal) increases the probability of a response (e.g., dependence-induced drug intake). These three stages are conceptualized as interacting with each other, becoming more intense, and ultimately leading to the pathological state known as addiction (Koob and Le Moal, 1997) (Table 1). The present review will focus on the role of an animal model of compulsivity that derives from the negative emotional state of the withdrawal/negative affect stage of the addiction cycle.

Table 1 
Stages of the addiction cycle.

Different drugs produce different patterns of addiction with emphasis on different components of the addiction cycle. Opioids can be considered classic drugs of addiction because subjects meet most of the criteria classically associated with addiction, including dramatic tolerance and withdrawal. A pattern of intravenous or smoked drug-taking evolves, including intense intoxication, the development of tolerance, escalation in intake, and profound dysphoria, physical discomfort, and somatic withdrawal signs during abstinence. Intense preoccupation with obtaining opioids (craving) develops that often precedes the somatic signs of withdrawal and is linked not only to stimuli associated with obtaining the drug but also to stimuli associated with withdrawal and the aversive motivational state. A pattern develops where the drug must be obtained to avoid the severe dysphoria and discomfort of abstinence. Other drugs of abuse follow a similar pattern but may involve more the binge/intoxication stage (psychostimulants and alcohol) or less binge/intoxication and more withdrawal/negative affect and preoccupation/anticipation stages (nicotine and cannabinoids).

Alcohol addiction, or alcoholism, can follow a similar trajectory, but the pattern of oral drug taking is often characterized by binges of alcohol intake that can be daily episodes or prolonged days of heavy drinking and is characterized by a severe emotional and somatic withdrawal syndrome. Many alcoholics continue with such a binge/withdrawal pattern for extended periods, but some individuals can evolve into an opioid-like situation in which they must have alcohol available at all times to avoid the negative consequences of abstinence. Tobacco addiction contrasts with the above patterns—the binge/intoxication stage forms a minor component of nicotine dependence. The pattern of nicotine intake is one of highly titrated intake of the drug except during periods of sleep. However, during abstinence, users experience negative emotional states, including dysphoria, irritability, and intense craving. Marijuana Dependence follows a pattern similar to opioids and tobacco, with a significant intoxication stage, but as chronic use continues, subjects begin to show a pattern of use manifest by chronic intoxication during waking hours and withdrawal characterized by dysphoria, irritability, and sleep disturbances. Psychostimulants, such as cocaine and amphetamines, show a pattern focused on the binge/intoxication stage in which binges can be hours or days in duration and often are followed by a withdrawal (“crash”) characterized by extreme dysphoria and inactivity.

1.1. Motivation, withdrawal, and opponent process

Motivation is a state that can be defined as a “tendency of the whole animal to produce organized activity” (Hebb, 1972), and such motivational states are not constant but rather vary over time. Early work by Wikler stressed the role of changes in drive states associated with dependence. Subjects described withdrawal changes as a “hunger” or primary need and the effects of morphine on such a state as “satiation” or gratification of the primary need (Wikler, 1952). Although Wikler argued that positive reinforcement was retained even in heavily dependent subjects (thrill of the intravenous opioid injection), dependence produced a new source of gratification, that of negative reinforcement (see above).

The concept of motivation was linked inextricably with hedonic, affective, or emotional states in addiction in the context of temporal dynamics by Solomon’s opponent process theory of motivation. Solomon and Corbit (1974) postulated that hedonic, affective, or emotional states, once initiated, are automatically modulated by the central nervous system with mechanisms that reduce the intensity of hedonic feelings. The a-process includes affective or hedonic habituation (or tolerance), and the b-process includes affective or hedonic withdrawal (abstinence). The a-process in drug use consists of positive hedonic responses, occurs shortly after presentation of a stimulus, correlates closely with the intensity, quality, and duration of the reinforcer, and shows tolerance. In contrast, the b-process in drug use appears after the a-process has terminated, consists of negative hedonic responses, and is sluggish in onset, slow to build up to an asymptote, slow to decay, and gets larger with repeated exposure. The thesis here is that opponent processes begin early in drug-taking, reflect changes in the brain reward and stress systems, and later form one of the major motivations for compulsivity in drug taking.

Thus, dependence or manifestation of a withdrawal syndrome after removal of chronic drug administration is defined in terms of motivational aspects of dependence such as emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) when access to the drug is prevented (Koob and Le Moal, 2001), rather than on the physical signs of dependence. Indeed, some have argued that the development of such a negative affective state can define dependence as it relates to addiction:

“The notion of dependence on a drug, object, role, activity or any other stimulus-source requires the crucial feature of negative affect experienced in its absence. The degree of dependence can be equated with the amount of this negative affect, which may range from mild discomfort to extreme distress, or it may be equated with the amount of difficulty or effort required to do without the drug, object, etc” (Russell, 1976).

Rapid acute tolerance and opponent process-like effects in response to the hedonic effects of cocaine have been reported in human studies of smoked coca paste (Van Dyke and Byck, 1982) (Figure 1A). After a single smoking session, the onset and intensity of the “high” are very rapid via the smoked route of administration, and a rapid tolerance is manifest. The “high” decreases rapidly despite significant blood levels of cocaine. Even more intriguing is that human subjects also actually report a subsequent “dysphoria,” again despite high blood levels of cocaine. Intravenous cocaine produced similar patterns of a rapid “rush” followed by an increased “low” in human laboratory studies (Breiter et al., 1997) (Figure 1B). With intravenous cocaine self-administration in animal models, such elevations in reward threshold begin rapidly and can be observed within a single session of self-administration (Kenny et al., 2003) (Figure 2), bearing a striking resemblance to human subjective reports. These results demonstrate that the elevation in brain reward thresholds following prolonged access to cocaine failed to return to baseline levels between repeated, prolonged exposure to cocaine self-administration (i.e., residual hysteresis), thus creating a greater and greater elevation in “baseline” ICSS thresholds. These data provide compelling evidence for brain reward dysfunction in escalated cocaine self-administration that provide strong support for a hedonic allostasis model of drug addiction.

Figure 1Figure 1 
(A) Dysphoric feelings followed the initial euphoria in experimental subjects who smoked cocaine paste, even though the concentration of cocaine in the plasma of the blood remained relatively high. The dysphoria is characterized by anxiety, depression, ...
Figure 2 
Rats (n = 11) were allowed to self-administer 10, 20, 40, and 80 injections of cocaine (0.25 mg per injection), and intracranial self-stimulation reward thresholds were measured 15 min and 2, 24, and 48 h after the end of each intravenous cocaine self-administration ...

Similar results have been observed showing dysphoria-like responses accompanying acute opioid and ethanol withdrawal (Liu and Schulteis, 2004; Schulteis and Liu, 2006). Here, naloxone administration following single injections of morphine increased reward thresholds, measured by ICSS, and increased thresholds with repeated morphine and naloxone-induced withdrawal experience (Liu and Schulteis, 2004). Similar results were observed during repeated acute withdrawal from ethanol (Schulteis and Liu, 2006).

The dysregulation of brain reward function associated with withdrawal from chronic administration of drugs of abuse is a common element of all drugs of abuse. Withdrawal from chronic cocaine (Markou and Koob, 1991), amphetamine (Paterson et al., 2000), opioids (Schulteis et al., 1994), cannabinoids (Gardner and Vorel, 1998), nicotine (Epping-Jordan et al., 1998), and ethanol (Schulteis et al., 1995) leads to increases in reward threshold during acute abstinence, and some of these elevations in threshold can last for up to one week (Figure 3). These observations lend credence to the hypothesis that opponent processes can set the stage for one aspect of compulsivity where negative reinforcement mechanisms are engaged.

Figure 3 
(A) Effects of ethanol withdrawal on CRF-like immunoreactivity (CRF-L-IR) in the rat amygdala determined by microdialysis. Dialysate was collected over four 2 h periods regularly alternated with nonsampling 2 h periods. The four sampling periods corresponded ...

More recently, opponent process theory has been expanded into the domains of the neurobiology of drug addiction from a neurocircuitry perspective. An allostatic model of the brain motivational systems has been proposed to explain the persistent changes in motivation that are associated with dependence in addiction (Koob and Le Moal 2001, 2008). In this formulation, addiction is conceptualized as a cycle of increasing dysregulation of brain reward/anti-reward mechanisms that results in a negative emotional state contributing to the compulsive use of drugs. Counteradaptive processes that are part of the normal homeostatic limitation of reward function fail to return within the normal homeostatic range. These counteradaptive processes are hypothesized to be mediated by two mechanisms: within-system neuroadaptations and between-system neuroadaptations (Koob and Bloom, 1988).

In a within-system neuroadaptation, “the primary cellular response element to the drug would itself adapt to neutralize the drug’s effects; persistence of the opposing effects after the drug disappears would produce the withdrawal response” (Koob and Bloom, 1988). Thus, a within-system neuroadaptation is a molecular or cellular change within a given reward circuit to accommodate overactivity of hedonic processing associated with addiction resulting in a decrease in reward function.

The emotional dysregulation associated with the withdrawal/negative affect stage also may involve between-system neuroadaptations in which neurochemical systems other than those involved in the positive rewarding effects of drugs of abuse are recruited or dysregulated by chronic activation of the reward system (Koob and Bloom, 1988). Thus, a between-system neuroadaptation is a circuitry change in which another different circuit (anti-reward circuit) is activated by the reward circuit and has opposing actions, again limiting reward function. The purpose of this review is to explore the neuroadaptational changes that occur in the brain emotional systems to account for the neurocircuitry changes that produce opponent processes and are hypothesized to have a key role in the compulsivity of addiction.

1.2. Animal models of compulsivity in addiction measured by negative emotional-like states: Place aversion, animal models of anxiety, and reward thresholds

Animal models of the withdrawal/negative affect stage include measures of conditioned place aversion (rather than preference) to precipitated withdrawal or spontaneous withdrawal from chronic administration of a drug, increases in reward thresholds using brain stimulation reward (Markou and Koob, 1991; Schulteis et al., 1994, 1995; Epping-Jordan et al., 1998; Gardner and Vorel, 1998; Paterson et al., 2000), and increases in anxiety-like responses (for review, see Shippenberg and Koob, 2002; Sanchis-Segura and Spanagel, 2006).

1.3. Animal models of compulsivity in addiction as defined by increased drug taking: Escalation in drug self-administration with prolonged access

A progressive increase in the frequency and intensity of drug use is one of the major behavioral phenomena characterizing the development of addiction and has face validity with the criteria of the Diagnostic and Statistical Manual of Mental Disorders: “The substance is often taken in larger amounts and over a longer period than was intended” (American Psychological Association, 1994). A framework with which to model the transition from drug use to drug addiction can be found in recent animal models of prolonged access to intravenous cocaine self-administration. Historically, animal models of cocaine self-administration involved the establishment of stable behavior from day to day to allow the reliable interpretation of data provided by within-subject designs aimed at exploring the neuropharmacological and neurobiological bases of the reinforcing effects of acute cocaine. Up until 1998, after acquisition of self-administration, rats typically were allowed access to cocaine for 3 h or less per day to establish highly stable levels of intake and patterns of responding between daily sessions. This was a useful paradigm for exploring the neurobiological substrates for the acute reinforcing effects of drugs of abuse.

However, in an effort to explore the possibility that differential access to intravenous cocaine self-administration in rats may produce different patterns of drug intake, rats were allowed access to intravenously self-administration cocaine for 1 or 6 h per day (Ahmed and Koob, 1998). One hour access (short access or ShA) to intravenous cocaine per session produced low and stable intake as observed previously. In contrast, 6 h access (long access or LgA) to cocaine produced drug intake that gradually escalated over days (Figure 4). Increased intake was observed in the extended access group during the first hour of the session, with sustained intake over the entire session and an upward shift in the dose-effect function, suggesting an increase in hedonic set point. When animals were allowed access to different doses of cocaine, both the LgA and ShA animals titrated their cocaine intake, but the LgA rats consistently self-administered almost twice as much cocaine at any dose tested, further suggesting an upward shift in the set point for cocaine reward in the escalated animals (Ahmed and Koob, 1999; Deroche-Gamonet et al., 2004; Mantsch et al., 2004). Escalation also is associated with an increase in break point for cocaine in a progressive-ratio schedule of reinforcement, suggesting an enhanced motivation to seek cocaine or an enhanced efficacy of cocaine reward (Paterson and Markou, 2003; Wee et al., 2008). Such increased self-administration in dependent animals has now been observed with cocaine, methamphetamine, nicotine, heroin, and alcohol (Ahmed et al., 2000; Ahmed and Koob, 1998; Kitamura et al., 2006; O’Dell et al., 2004; George et al., 2007) (Figure 4). This model is a key element for evaluating the motivational significance of opponent process changes in the brain reward and stress systems in addiction that lead to compulsivity in addiction. Similar changes in the reinforcing and incentive effects of cocaine as drug intake have been observed following extended access and include increased cocaine-induced reinstatement after extinction and a decreased latency to goal time in a runway model for cocaine reward (Deroche et al., 1999). Altogether, these results suggest that drug taking with extended access changes the motivation to seek the drug. Whether this enhanced drug taking reflects a sensitization of reward or a reward deficit state remains under discussion (Vezina, 2004), but the brain reward and neuropharmacological studies outlined below argue for a reward deficit state driving the increased drug taking during extended access.

Figure 4 
(A) Effect of drug availability on cocaine intake (mean ± SEM). In 6 h long-access (LgA) rats (n = 12) but not in 1 h short-access (ShA) rats (n = 12), mean total cocaine intake started to increase significantly from session 5 (p < 0.05; ...

The hypothesis that compulsive cocaine use is accompanied by a chronic perturbation in brain reward homeostasis has been tested in an animal model of escalation in drug intake with prolonged access combined with measures of brain stimulation reward thresholds. Animals implanted with intravenous catheters and allowed differential access to intravenous self-administration of cocaine showed increases in cocaine self-administration from day to day in the long-access group (6 h; LgA) but not in the short-access group (1 h; ShA). The differential exposure to cocaine self-administration had dramatic effects on reward thresholds that progressively increased in LgA rats but not in ShA or control rats across successive self-administration sessions (Ahmed et al., 2002). Elevation in baseline reward thresholds temporally preceded and was highly correlated with escalation in cocaine intake (Figure 5). Post-session elevations in reward thresholds failed to return to baseline levels before the onset of each subsequent self-administration session, thereby deviating more and more from control levels. The progressive elevation in reward thresholds was associated with the dramatic escalation in cocaine consumption that was observed previously. After escalation had occurred, an acute cocaine challenge facilitated brain reward responsiveness to the same degree as before but resulted in higher absolute brain reward thresholds in LgA compared with ShA rats (Ahmed et al., 2002). Similar results have been observed with extended access to heroin (Kenny et al., 2006). Rats allowed 23 h access to heroin also showed a time-dependent increase in reward thresholds that paralleled the increases in heroin intake (Figure 5).

Figure 5Figure 5 
(A) Relationship between elevation in intracranial self-stimulation reward thresholds and cocaine intake escalation. (Left) Percentage change from baseline ICSS thresholds. (Right) Number of cocaine injections earned during the first hour of each session. ...

2. Neural substrates for the negative emotional state associated with addiction

2.1. Within-system neuroadaptations that contribute to the negative emotional state component of compulsivity

Electrical brain stimulation reward or intracranial self-stimulation has a long history as a measure of activity of the brain reward system and of the acute reinforcing effects of drugs of abuse. All drugs of abuse, when administered acutely, decrease brain stimulation reward thresholds (Kornetsky and Esposito, 1979) and when administered chronically increase reward thresholds during withdrawal (see above). Brain stimulation reward involves widespread neurocircuitry in the brain, but the most sensitive sites defined by the lowest thresholds involve the trajectory of the medial forebrain bundle that connects the ventral tegmental area with the basal forebrain (Olds and Milner, 1954; Koob et al., 1977). While much emphasis was focused initially on the role of the ascending monoamine systems in the medial forebrain bundle, other nondopaminergic systems in the medial forebrain bundle clearly have a key role (Hernandez et al., 2006).

Within-system neuroadaptations to chronic drug exposure include decreases in function of the same neurotransmitter systems in the same neurocircuits implicated in the acute reinforcing effects of drugs of abuse. One prominent hypothesis is that dopamine systems are compromised in crucial phases of the addiction cycle, such as withdrawal and leads to decreased motivation for non-drug-related stimuli and increased sensitivity to the abused drug (Melis et al., 2005). Activation of the mesolimbic dopamine system has long been known to be critical for the acute rewarding properties of psychostimulant drugs and to be associated with the acute reinforcing effects of other drugs of abuse (Koob, 1992; Di Chiara and North, 1992; Nestler, 2005). Decreases in activity of the mesolimbic dopamine system and decreases in serotonergic neurotransmission in the nucleus accumbens occur during drug withdrawal in animal studies (Rossetti et al., 1992; Weiss et al., 1992, 1996). Imaging studies in drug-addicted humans have consistently shown long-lasting decreases in the numbers of dopamine D2 receptors in drug abusers compared with controls (Volkow et al., 2002). In addition, cocaine abusers have reduced dopamine release in response to a pharmacological challenge with a stimulant drug (Volkow et al., 1997; Martinez et al., 2007). Decreases in the number of dopamine D2 receptors, coupled with the decrease in dopaminergic activity, in cocaine, nicotine, and alcohol abusers results in decreased sensitivity of reward circuits to stimulation by natural reinforcers (Martin-Solch et al., 2001; Volkow and Fowler, 2000). These findings suggest an overall reduction in the sensitivity of the dopamine component of reward circuitry to natural reinforcers and other drugs in drug-addicted individuals.

Psychostimulant withdrawal in humans is associated with fatigue, decreased mood, and psychomotor retardation and in animals is associated with decreased motivation to work for natural rewards (Barr and Phillips, 1999) and decreased locomotor activity (Pulvirenti and Koob, 1993), behavioral effects that may involve decreased dopaminergic function. Animals during amphetamine withdrawal show decreased responding on a progressive-ratio schedule for a sweet solution, and this decreased responding was reversed by the dopamine partial agonist terguride (Orsini et al., 2001), suggesting that low dopamine tone contributes to the motivational deficits associated with psychostimulant withdrawal.

Under this conceptual framework, other within-system neuroadaptations would include increased sensitivity of receptor transduction mechanisms in the nucleus accumbens. Drugs of abuse have acute receptor actions that are linked to intracellular signaling pathways that may undergo adaptations with chronic treatment. Activation of adenylate cyclase, protein kinase A, cyclic adenosine monophosphate response-element binding protein (CREB), and ΔFosB has been observed during opioid withdrawal (Self et al., 1995; Shaw-Lutchman et al., 2002; Nye and Nestler, 1996; Nestler, 2004). The ΔFosB response is hypothesized to represent a neuroadaptive change that extends long into protracted abstinence (Nestler and Malenka, 2004).

2.2. Between-system neuroadaptations that contribute to the negative emotional state component of compulsivity

Brain neurochemical systems involved in arousal-stress modulation also may be engaged within the neurocircuitry of the brain stress systems in an attempt to overcome the chronic presence of the perturbing drug and to restore normal function despite the presence of drug. Both the hypothalamic-pituitary-adrenal axis and the brain stress system mediated by corticotropin-releasing factor (CRF) are dysregulated by chronic administration of all major drugs with dependence or abuse potential, with a common response of elevated adrenocorticotropic hormone, corticosterone, and amygdala CRF during acute withdrawal (Rivier et al., 1984; Merlo-Pich et al., 1995; Koob et al., 1994; Rasmussen et al., 2000; Olive et al., 2002; Delfs et al., 2000). Acute withdrawal from all drugs of abuse also produces an aversive or anxiety-like state that can be reversed by CRF antagonists (see below).

The neuroanatomical entity termed the extended amygdala (Heimer and Alheid, 1991) may represent a common anatomical substrate integrating brain arousal-stress systems with hedonic processing systems to produce the between-system opponent process elaborated above. The extended amygdala is composed of the central nucleus of the amygdala, bed nucleus of the stria terminalis, and a transition zone in the medial (shell) subregion of the nucleus accumbens. Each of these regions has cytoarchitectural and circuitry similarities (Heimer and Alheid, 1991). The extended amygdala receives numerous afferents from limbic structures such as the basolateral amygdala and hippocampus and sends efferents to the medial part of the ventral pallidum and a large projection to the lateral hypothalamus, thus further defining the specific brain areas that interface classical limbic (emotional) structures with the extrapyramidal motor system (Alheid et al., 1995). The extended amygdala has long been hypothesized to have a key role not only in fear conditioning (Le Doux, 2000) but also in the emotional component of pain processing (Neugebauer et al., 2004).

2.3. Neuropharmacological studies of the aversive stimulus effects of drug withdrawal

Place aversion has been used to measure the aversive stimulus effects of withdrawal, mostly in the context of opioids (Hand et al., 1988; Stinus et al., 1990). In contrast to conditioned place preference, rats exposed to a particular environment while undergoing precipitated withdrawal to opioids spend less time in the withdrawal-paired environment when subsequently presented with a choice between that environment and an unpaired environment. These aversive stimulus effects can be measured from 24 h to 16 weeks later (Hand et al., 1988; Stinus et al., 1990, 2000). The place aversion does not require maintenance of opioid dependence for its manifestation. Such an association continues to be manifested weeks after animals are “detoxified” (e.g., after the morphine pellets are removed) (see Baldwin and Koob, 1993; Stinus et al., 2000). In addition, a place aversion in opioid-dependent rats can be observed with doses of naloxone below which somatic signs of withdrawal are observed (Schulteis et al., 1994). Although naloxone itself will produce a place aversion in nondependent rats, the threshold dose required to produce a place aversion decreases significantly in dependent rats (Hand et al., 1988). A variant on this approach is to explore the place aversion produced following naloxone injection after a single acute injection of morphine.

Acute opioid dependence has been defined as the precipitation of withdrawal-like signs by opioid antagonists following a single dose or short-term administration of an opioid agonist (Martin and Eades, 1964). Rats show a reliable conditioned place aversion precipitated by a low dose of naloxone after a single morphine injection that reflects a motivational component of acute withdrawal (Azar et al., 2003). Acute opioid withdrawal also produces increases in reward thresholds (Liu and Schulteis, 2004), suppression in operant responding (Schulteis et al., 2003) and increased anxiety-like behavior in the elevated plus maze (Zhang and Schulteis, 2008). Using the conditioned place aversion paradigm, the opioid partial agonist buprenorphine dose-dependently decreased the place aversion produced by precipitated opioid withdrawal. Systemic administration of a CRF1 receptor antagonist and direct intracerebral administration of a peptide CRF1/CRF2 antagonist also decreased opioid withdrawal-induced place aversions (Stinus et al., 2005; Heinrichs et al., 1995). Functional noradrenergic antagonists blocked opioid withdrawal-induced place aversion (Delfs et al., 2000).

Another candidate for the aversive effects of drug withdrawal is dynorphin. Much evidence shows that dynorphin is increased in the nucleus accumbens in response to dopaminergic activation and, in turn, that overactivity of the dynorphin systems can decrease dopaminergic function. κ opioid agonists are aversive (Land et al., 2008; Pfeiffer et al., 1986), and cocaine, opioid, and ethanol withdrawal is associated with increased dynorphin in the nucleus accumbens and/or amygdala (Spangler et al., 1993; Lindholm et al., 2000; Rattan et al., 1992).

2.4. Neuropharmacological studies of the anxiety-like effects of drug withdrawal

Another common response to acute withdrawal and protracted abstinence from all major drugs of abuse is the manifestation of anxiety-like responses. Animal models have revealed anxiety-like response to all major drugs of abuse during acute withdrawal. The dependent variable is often a passive response to a novel and/or aversive stimulus, such as the open field or elevated plus maze, or an active response to an aversive stimulus, such as defensive burying of an electrified metal probe. Withdrawal from repeated administration of cocaine produces an anxiogenic-like response in the elevated plus maze and defensive burying test, both of which are reversed by administration of CRF antagonists (Sarnyai et al., 1995; Basso et al., 1999). Precipitated withdrawal in opioid dependence also produces anxiety-like effects (Schulteis et al., 1998; Harris and Aston-Jones, 1993). Ethanol withdrawal produces anxiety-like behavior that is reversed by intracerebroventricular administration of CRF1/CRF2 peptidergic antagonists (Baldwin et al., 1991), small molecule CRF1 antagonist (Knapp et al., 2004; Overstreet et al., 2004; Funk et al., 2007), and intracerebral administration of a peptidergic CRF1/CRF2 antagonist into the amygdala (Rassnick et al., 1993). CRF antagonists injected intracerebroventricularly or systemically also block the potentiated anxiety-like responses to stressors observed during protracted abstinence from chronic ethanol (Breese et al., 2005; Valdez et al., 2003). The effects of CRF antagonists have been localized to the central nucleus of the amygdala (Rassnick et al., 1993). Precipitated withdrawal from nicotine produces anxiety-like responses that are also reversed by CRF antagonists (Tucci et al., 2003; George et al., 2007).

3. Neural Substrates for Increased Drug-taking with Extended Access

3.1. Within-system neuroadaptations

In a series of studies, dopamine partial agonists have not only been shown to reverse psychostimulant withdrawal but also to block the increase in psychostimulant self-administration associated with extended access. Dopamine partial agonists decrease the reinforcing effects of psychostimulant drugs in nondependent limited access paradigms (Izzo et al., 2001; Pulvirenti et al., 1998). However, animals with extended access show an increased sensitivity to a dopamine partial agonist (Wee et al., 2007). Long-access rats administered a dopamine D2 partial agonist showed a shift to the left of the dose-response function similar to results observed with dopamine antagonists (Ahmed and Koob, 2004). These results, combined with the observation that dopamine partial agonists also can reverse psychostimulant withdrawal, suggest that dysregulation of dopamine tone may contribute to the motivational effects of drug withdrawal.

Similar results have been observed in opioid dependence with the opioid partial agonist buprenorphine. Buprenorphine dose-dependently decreased heroin self-administration in opioid-dependent rats (Chen et al., 2006).

3.2. Between-system neuroadaptations

The ability of CRF antagonists to block the anxiogenic-like and aversive-like motivational effects of drug withdrawal would predict motivational effects of CRF antagonists in animal models of extended access to drugs. CRF antagonists selectively blocked the increased self-administration of drugs associated with extended access to intravenous self-administration of cocaine (Specio et al., 2008), nicotine (George et al., 2007), and heroin (Greenwell et al., 2008a). CRF antagonists also blocked the increased self-administration of ethanol in dependent rats (Funk et al., 2007) (Table 2).

Table 2 
Role of corticotropin-releasing factor in dependence.

Administration of CRF1 antagonists systemically reversed the increased self-administration of cocaine associated with extended access, and this reversal was at antagonist doses that were lower than those that decreased short-access self-administration (Specio et al., 2008). Here, rats allowed 6 h access to cocaine showed an increase in cocaine intake over time, whereas 1 h access rats remained stable. Two different CRF1 antagonists blocked cocaine self-administration in the long-access rats at doses lower than those that blocked cocaine self-administration in short-access rats (Specio et al., 2008).

As noted above, CRF in parts of the extended amygdala is involved in the aversive stimulus effects of opioid withdrawal. The selective CRF1 antagonist antalarmin blocked the place aversion produced by naloxone in morphine-dependent rats (Stinus et al., 2005). CRF1 knockout mice failed to show conditioned place aversion to opioid withdrawal and failed to show an opioid-induced increase in dynorphin mRNA in the nucleus accumbens (Contarino and Papaleo, 2005). CRF1 antagonists also selectively blocked the increase in heroin self-administration observed in heroin-dependent rats with extended access (Greenwell et al., 2008a).

Also, as noted above, precipitated withdrawal from chronic nicotine produced anxiogenic-like effects that were blocked by a CRF1 receptor antagonist (George et al., 2007) and increases in reward thresholds that were reversed by a CRF antagonist (Bruijnzeel et al., 2007). Extracellular CRF has been shown to be increased in the amygdala during withdrawal from chronic nicotine (George et al., 2007). From a developmental perspective, increased CRF-like immunoreactivity has been observed in adult rats exposed to nicotine during adolescence and has been linked to an anxiety-like phenotype (Slawecki et al., 2005). Systemic administration of a CRF1 antagonist blocked the increased self-administration of nicotine associated with withdrawal in extended access (23 h) animals (George et al., 2007). These results suggest that CRF in the basal forebrain also may have an important role in the development of the aversive motivational effects that drive the increased drug seeking associated with cocaine, heroin, and nicotine dependence.

A particularly dramatic example of the motivational effects of CRF in dependence can be observed in animal models of ethanol self-administration in dependent animals. During ethanol withdrawal, extrahypothalamic CRF systems become hyperactive, with an increase in extracellular CRF within the central nucleus of the amygdala and bed nucleus of the stria terminalis of dependent rats (Funk et al., 2006; Merlo-Pich et al., 1995; Olive et al., 2002). The dysregulation of brain CRF systems is hypothesized to underlie not only the enhanced anxiety-like behaviors but also the enhanced ethanol self-administration associated with ethanol withdrawal. Supporting this hypothesis, the -helical CRF9–41 and D-Phe CRF12–41 (intracerebroventricular administration) reduce ethanol self-administration in dependent animals (Valdez et al., 2004). Exposure to repeated cycles of chronic ethanol vapor produced substantial increases in ethanol intake in rats both during acute withdrawal and during protracted abstinence (2 weeks post-acute withdrawal) (O’Dell et al., 2004; Rimondini et al., 2002). Intracerebroventricular administration of a CRF1/CRF2 antagonist blocked the dependence-induced increase in ethanol self-administration during both acute withdrawal and protracted abstinence (Valdez et al., 2004). When administered directly into the central nucleus of the amygdala, a CRF1/CRF2 antagonist blocked ethanol self-administration in ethanol-dependent rats (Funk et al., 2006, 2007). Systemic injections of small-molecule CRF1 antagonists also blocked the increased ethanol intake associated with acute withdrawal (Knapp et al., 2004; Overstreet et al., 2004; Funk et al., 2007). These data suggest an important role for CRF, primarily within the central nucleus of the amygdala, in mediating the increased self-administration associated with dependence.

Although less well developed, evidence exists for a role of norepinephrine systems in the extended amygdala in the negative motivational state and increased self-administration associated with dependence. Norepinephrine functional antagonists (β1 antagonist and α2 agonist) injected into the lateral bed nucleus of the stria terminalis blocked precipitated opiate withdrawal-induced place aversions (Delfs et al., 2000). The effects of norepinephrine in mediating the motivational effects of opioid withdrawal involve the ventral noradrenergic system. Ventral noradrenergic bundle lesions attenuated opioid withdrawal-induced place aversions (Delfs et al., 2000), but virtually complete lesions of the dorsal noradrenergic bundle from the locus coeruleus with the neurotoxin 6-hydroxydopamine failed to block the place aversion produced by opioid withdrawal (Caille et al., 1999). Functional norepinephrine antagonists block excessive drug intake associated with dependence on ethanol (Walker et al., 2008), cocaine (Wee et al., 2008), and opioids (Greenwell et al., 2008b). A focal point for many of these effects is the extended amygdala but at the level of the bed nucleus of the stria terminalis. κ Dynorphin, an opioid peptide that binds to κ opioid receptors, has long been known to show activation with chronic administration of psychostimulants and opioids (Nestler, 2004; Koob, 2008), and κ opioid agonists produce aversive effects in animals and humans (Mucha and Herz, 1985; Pfeiffer et al., 1986). A κ opioid antagonist blocks the excessive drinking associated with ethanol withdrawal and dependence (Walker and Koob, 2008). Evidence demonstrates that κ receptor activation can produce CRF release (Song and Takemori, 1992), but recently some have argued that the effects of dynorphin in producing negative emotional states are mediated via activation of CRF systems (Land et al., 2008).

The dynamic nature of the brain stress system response to challenge is illustrated by the pronounced interaction of central nervous system CRF systems and central nervous system norepinephrine systems. Conceptualized as a feed-forward system at multiple levels of the pons and basal forebrain, CRF activates norepinephrine, and norepinephrine in turn activates CRF (Koob, 1999). Much pharmacologic, physiologic, and anatomic evidence supports an important role for a CRF-norepinephrine interaction in the region of the locus coeruleus in response to stressors (Valentino et al., 1991, 1993; Van Bockstaele et al., 1998). However, norepinephrine also stimulates CRF release in the paraventricular nucleus of the hypothalamus (Alonso et al., 1986), the bed nucleus of the stria terminalis, and the central nucleus of the amygdala. Such feed-forward systems were further hypothesized to have powerful functional significance for mobilizing an organism’s response to environmental challenge, but such a mechanism may be particularly vulnerable to pathology (Koob, 1999).

Neuropeptide Y (NPY) is a neuropeptide with dramatic anxiolytic-like properties localized to the amygdala and has been hypothesized to have opposite effects to CRF in the negative motivational state of withdrawal from drugs of abuse (Heilig and Koob, 2007). Significant evidence suggests that activation of NPY in the central nucleus of the amygdala can block the motivational aspects of dependence associated with chronic ethanol administration. NPY administered intracerebroventricularly blocked the increased drug intake associated with ethanol dependence (Thorsell et al., 2005a, b). Injection of NPY directly into the central nucleus of the amygdala (Gilpin et al., 2008) and viral vector-enhanced expression of NPY in the central nucleus of the amygdala also blocked the increased drug intake associated with ethanol dependence (Thorsell et al., 2007).

Thus, acute withdrawal from drugs increases CRF in the central nucleus of the amygdala that has motivational significance for the anxiety-like effects of acute withdrawal and the increased drug intake associated with dependence (Figure 6). Acute withdrawal also may increase the release of norepinephrine in the bed nucleus of the stria terminalis and dynorphin in the nucleus accumbens, and both of which may contribute to the negative emotional state associated with dependence. Decreased activity of NPY in the central nucleus of the amygdala also may contribute to the anxiety-like state associated with ethanol dependence. Activation of brain stress systems (CRF, norepinephrine, dynorphin) combined with inactivation of brain anti-stress systems (NPY) elicits powerful emotional dysregulation in the extended amygdala. Such dysregulation of emotional processing may be a significant contribution to the between-system opponent processes that help maintain dependence and also set the stage for more prolonged state changes in emotionality such as protracted abstinence.

Figure 6 
Neurocircuitry associated with the acute positive reinforcing effects of drugs of abuse and the negative reinforcement of dependence and how it changes in the transition from nondependent drug taking to dependent drug taking. Key elements of the reward ...

4. Compulsivity in addiction: An allostatic view

Compulsivity in addiction can derive from multiple sources, including enhanced incentive salience, engagement of habit function, and impairment in executive function. However, underlying each of these sources is a negative emotional state that may strongly impact on compulsivity. The development of the negative emotional state that drives the negative reinforcement of addiction has been defined as the “dark side” of addiction (Koob and Le Moal, 2005, 2008) and is hypothesized to be the b-process of the hedonic dynamic known as opponent process when the a-process is euphoria. The negative emotional state that comprises the withdrawal/negative affect stage consists of key motivational elements, such as chronic irritability, emotional pain, malaise, dysphoria, alexithymia, and loss of motivation for natural rewards, and is characterized in animals by increases in reward thresholds during withdrawal from all major drugs of abuse. Two processes are hypothesized to form the neurobiological basis for the b-process: loss of function in the reward systems (within-system neuroadaptation) and recruitment of the brain stress or anti-reward systems (between-system neuroadaptation) (Koob and Bloom, 1988; Koob and Le Moal, 1997). Anti-reward is a construct based on the hypothesis that brain systems are in place to limit reward (Koob and Le Moal, 2008). As dependence and withdrawal develop, brain stress systems such as CRF, norepinephrine, and dynorphin are recruited, producing aversive or stress-like states (Koob, 2003; Nestler, 2001; Aston-Jones et al., 1999). At the same time, within the motivational circuits of the ventral striatum-extended amygdala, reward function decreases. The combination of decreases in reward neurotransmitter function and recruitment of anti-reward systems provides a powerful source of negative reinforcement that contributes to compulsive drug-seeking behavior and addiction (Figure 6).

An overall conceptual theme argued here is that drug addiction represents a break with homeostatic brain regulatory mechanisms that regulate the emotional state of the animal. The dysregulation of emotion begins with the binge and subsequent acute withdrawal, but leaves a residual neuroadaptive trace that allows rapid “re-addiction” even months and years after detoxification and abstinence. Thus, the emotional dysregulation of drug addiction represents more than simply a homeostatic dysregulation of hedonic function; it also represents a dynamic break with homeostasis of this system that has been termed allostasis.

Allostasis, originally conceptualized to explain persistent morbidity of arousal and autonomic function, is defined as “stability through change.” Allostasis is far more complex than homeostasis and has several unique characteristics (Sterling and Eyer, 1988). Allostasis involves a feed-forward mechanism rather than the negative feedback mechanisms of homeostasis, with continuous re-evaluation of need and continuous readjustment of all parameters toward new set points. An allostatic state can be defined as a state of chronic deviation of the regulatory system from its normal (homeostatic) operating level. Allostatic load was defined as the “long-term cost of allostasis that accumulates over time and reflects the accumulation of damage that can lead to pathological states” (McEwen, 2000).

Allostatic mechanisms have been hypothesized to be involved in maintaining a functioning brain reward system that has relevance for the pathology of addiction (Koob and Le Moal, 2001). Two components are hypothesized to adjust to challenges to the brain produced by drugs of abuse: overactivation of brain reward transmitters and circuits and recruitment of the brain anti-reward or brain stress systems. Thus, the very physiological mechanism that allows rapid responses to environmental challenge becomes the source of pathology if adequate time or resources are not available to shut off the response (e.g., the interaction between CRF and norepinephrine in the brainstem and basal forebrain that could lead to pathological anxiety) (Koob, 1999).

Repeated challenges, such as with drugs of abuse, lead to attempts of the brain via molecular, cellular, and neurocircuitry changes to maintain stability but at a cost. For the drug addiction framework elaborated here, the residual deviation from normal brain reward threshold regulation is termed an allostatic state. This state represents a combination of chronic elevation of reward set point fueled by decreased function of reward circuits and recruitment of anti-reward systems, both of which lead to the compulsivity of drug-seeking and drug-taking. How these systems are modulated by other known brain emotional systems localized to the basal forebrain, where the ventral striatum and extended amygdala project to convey emotional valence, how the dysregulation of brain emotional systems impact on the cognitive domain linked to impairments in executive function, and how individuals differ at the molecular-genetic level of analysis to convey loading on these circuits remain challenges for future research.

Acknowledgments

The author would like to thank Michael Arends and Mellany Santos for their outstanding assistance with the preparation of this manuscript. Research was supported by National Institutes of Health grants AA06420 and AA08459 from the National Institute on Alcohol Abuse and Alcoholism, DA10072, DA04043, and DA04398 from the National Institute on Drug Abuse, and DK26741 from the National Institute of Diabetes and Digestive and Kidney Diseases. Research also was supported by the Pearson Center for Alcoholism and Addiction Research. This is publication number 19480 from The Scripps Research Institute.

Footnotes

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