Stress 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".
By 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.
Important 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.
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.
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.
“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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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
BY: LEIGH MACMILLAN
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.
Front Neurosci. 2012; 6: 157. Published online 2012 November 1. doi: 10.3389/fnins.2012.00157
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.
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.
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=23.41years, 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.
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 2min 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.
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 2s, representing a number between 1 and 9 (Figure (Figure1A).1A). Their task was to make a button press during those 2s 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 2s choice phase, the actual number appeared on the card for 2s (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 2s 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 12s, followed by the next trial.
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 10min. 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).
Participants were instructed to avoid eating, drinking (anything other than water), or smoking for 2h 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 1min 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 15min 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.
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=256mm, 176 1mm axial slices) were obtained from all subjects. Functional images (single-shot gradient echo EPI sequence; TR=2000ms; TE=25ms; FOV=192cm; flip angle=80°; matrix=64×64; slice thickness=3mm) 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 53mm 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).
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.
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 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,
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.
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.
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,
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.
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,
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 15min 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.
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.
This research was supported by funding from the National Institute on Drug Abuse to Mauricio R. Delgado (R01DA027764).
Front Psychiatry. 2013; 4: 72.
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.
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.
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.
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).
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 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).
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).
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).
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 1week (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).
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).
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 3h 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 6h 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).
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.
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 (6h; LgA) but not in the ShA group (1h; 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 6h access to methamphetamine or 23h 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).
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].
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 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).
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 (23h) animals (77).
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 [2weeks 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.
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.
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).
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<10s), increasing the working memory load (i.e., close to the capacity limit of working memory) by increasing the delay from 10 to 70 and 130s 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 (24h per day, 7days per week) or intermittent (3days 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 (24–72h) but not protracted (16–68days) 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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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).
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).
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).
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.
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).
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).
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.
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).
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).
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).
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.
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.
COMMENT: Stress can increase vulnerability to 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: email@example.com
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.
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.
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
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.
Preparation of this review was supported by grants from the National Institutes of Health, P50-DA165556, R01-AA13892, R01-DA18219, and U01-RR24925.
Conflicts of Interest
The author declares no conflicts of interest.
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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: firstname.lastname@example.org
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
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.
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).
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.
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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Behav Brain Res. 2013 May 16. pii: S0166-4328(13)00283-0. doi: 10.1016/j.bbr.2013.05.012. [Epub ahead of print]
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.
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.
Nature (2012) doi:10.1038/nature11436
Received 13 May 2011Published online 19 September 2012
Stressors motivate an array of adaptive responses ranging from ‘fight or flight’ to an internal urgency signal facilitating long-term goals1. However, traumatic or chronic uncontrollable stress promotes the onset of major depressive disorder, in which acute stressors lose their motivational properties and are perceived as insurmountable impediments2. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal3. An emerging neurobiological substrate of depression and associated pathology is the nucleus accumbens, a region with the capacity to mediate a diverse range of stress responses by interfacing limbic, cognitive and motor circuitry4. Here we report that corticotropin-releasing factor (CRF), a neuropeptide released in response to acute stressors5 and other arousing environmental stimuli6, acts in the nucleus accumbens of naive mice to increase dopamine release through coactivation of the receptors CRFR1 and CRFR2. Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days. This loss of CRF’s capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors. Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.
It may come as no surprise that stressful life events often precede episodes of major depressive disorder. But what might surprise you is that, in general, scientists have had little understanding of exactly why that is.
The new study, carried out in mice and published this week in the journal Nature, makes significant progress toward that goal. The researchers, from the University of Washington, identified the missing link: a peptide called corticotropin-releasing factor, or CRF. CRF, they discovered, plays a nuanced role in an area of the brain called the nucleus accumbens, a region well known for its role in motivation, pleasure and social behavior.
Normally, the brain signaling pathways in the nucleus accumbens work like this: When something exciting or motivating happens, such as entering a new environment or receiving a new toy to play with, CRF arrives and binds to a receptor. This causes an increase in the release of dopamine-a neurotransmitter that plays a major role in making you feel rewarded or aroused by something interesting in your environment.
The researchers demonstrated this with a standard experimental design called "conditioned place preference." They put a mouse in one of two connected cages and infused its nucleus accumbens with CRF. Then, the researchers moved the mouse to the other cage, and infused their nucleus accumbens with a placebo liquid. After that, they let the mouse choose which cage it preferred. If CRF was leading to dopamine release -- and thus to a strong feeling of reward -- the mouse should prefer the cage where it received CRF, even though in reality the cages are identical. That is exactly what they found.
The scientists then carried out the central experiment: They stressed the animals out by forcing them to swim in water numerous times over a two-day period, which has been shown in the past to not only be stressful but to lead mice to have symptoms of depression. Then they tested the ability of CRF to cause dopamine release in the brains of the stressed-out mice.
Incredibly, they found that the effect was completely gone: CRF no longer had an impact on the release of dopamine after stress. In fact, when the scientists repeated the cage test, they found that CRF actually caused the mice to want to spend less time in the cage, meaning the molecule had actually become aversive. The effect lasted for more than 90 days, suggesting it mirrors the long time-course of depressive disorder.
In other words, a chemical cascade that normally makes you feel good had been twisted to make you feel bad.
Front Mol Neurosci. 2012; 5: 91. Published online 2012 September 6. doi: 10.3389/fnmol.2012.00091
Corticotropin releasing factor (CRF) has been shown to induce various behavioral changes related to adaptation to stress. Dysregulation of the CRF system at any point can lead to a variety of psychiatric disorders, including substance use disorders (SUDs). CRF has been associated with stress-induced drug reinforcement. Extensive literature has identified CRF to play an important role in the molecular mechanisms that lead to an increase in susceptibility that precipitates relapse to SUDs. The CRF system has a heterogeneous role in SUDs. It enhances the acute effects of drugs of abuse and is also responsible for the potentiation of drug-induced neuroplasticity evoked during the withdrawal period. We present in this review the brain regions and circuitries where CRF is expressed and may participate in stress-induced drug abuse. Finally, we attempt to evaluate the role of modulating the CRF system as a possible therapeutic strategy for treating the dysregulation of emotional behaviors that result from the acute positive reinforcement of substances of abuse as well as the negative reinforcement produced by withdrawal.
Drug addiction is a chronic condition characterized by periods of abstinence and relapse. The effects of drugs of abuse on brain function have been extensively evaluated with the intention of developing therapies that can prevent relapse and facilitate the treatment of substance use disorders (SUDs). An extensive literature has shown that addictive drugs affect systems that govern reward pathways (mesolimbic dopaminergic pathway), learning and memory processes (hippocampus), emotion (amygdala), and cognitive functions (prefrontal cortex). The reinforcing effects of drug of abuse have been attributed to actions in the limbic system that in turn influence motivational, emotional and affective behaviors (Rezayof et al., 2002; David et al., 2008; Martin et al., 2008; Nielsen et al., 2011; Xue et al., 2012) and for reviews see (Koob, 1992; Pierce and Kumaresan, 2006; Feltenstein and See, 2008). Specifically, the alteration of reward processing (Wise, 1998, 2005) has been identified as a critical factor that leads to an increase in the chance of relapse (Koob and Le Moal, 1997; Everitt et al., 1999; Koob et al., 2004; Everitt and Robbins, 2005). The development of SUDs is a progression that commences with the first exposure to the drug and ends with physiological and psychological dependence.
Although substances of abuse have different mechanisms of action, repeated exposure has been shown to lead to similar neural adaptations. Addiction to any class of drugs has been described as a learning process. Individuals learn associations between the rewarding effects of the drugs and the environmental cues that predict drug availability. Neuroadaptations in areas associated with learning and memory (hippocampus and amygdala) are affected after a single episode of any drug use by influencing synaptic transmission. Following chronic drug use, the compulsive seeking and uncontrollable use leads to long-lasting alterations in synaptic plasticity, such as changes in synaptic strength.
Human studies (Gawin and Kleber, 1986; Wallace, 1989) and experiments with preclinical models (Thatcher-Britton and Koob, 1986; Piazza et al., 1990; Goeders and Guerin, 1994; Kreibich et al., 2009) have identified stress as a critical factor in the drug addiction process, including triggering relapse. Corticotropin releasing factor (CRF) has been implicated in neuroendocrine and behavioral responses to stress (Britton et al., 1982; Koob and Bloom, 1985). It has been shown to be activated during stress-induced drug reinstatement, where it acts to facilitate relapse and increase anxiety during acute and chronic withdrawal (Shaham et al., 1995; Ambrosio et al., 1997; Koob, 1999) and see (Sarnyai et al., 2001; George et al., 2011) for extensive review.
CRF-induced neuroplastic changes have been studied both in mesolimbic brain circuits that include the ventral tegmental area (VTA) and nucleus accumbens (NAcc) (Ungless et al., 2003; Wang et al., 2007a; Hahn et al., 2009) and also in brain regions associated with emotion, such as the amygdala (Fudge and Emiliano, 2003; Pollandt et al., 2006; Fu et al., 2007; Kash et al., 2008; Francesconi et al., 2009).
Despite extensive research supporting the role of CRF in drug addiction, the specific participation of CRF on drug-induced synaptic plasticity that leads to relapse remains undetermined.
This review will attempt to examine recent research on the role of CRF and its interaction with drug-mediated synaptic plasticity. The VTA and the amygdalar nuclei where CRF is highly expressed will be described. We will discuss whether CRF facilitates or inhibits synaptic strength from the basal condition. Finally, we will attempt to integrate the neurobiological changes that result from the interaction of substances of abuse with stress to evaluate alternative drug targets for experimental therapeutics to prevent relapse and facilitate the treatment of SUDs.
SUDs are a chronic and relapsing condition characterized by an intense desire for drug intake during the withdrawal period. This craving process leads to a progression from the initial impulsive consumption to a subsequent compulsive and habit forming consumption that result in loss of control in limiting intake and subsequent inability to change the habit developed over time. One of the main challenges in preclinical addiction research has been to elucidate the pathways that lead to the loss of control of drug use and the predisposition to relapse (Koob and Le Moal, 1997). As described by the Opponent Process Model, the repetitive use of addictive substances alters the reward circuits by decreasing the intense pleasure state and by increasing the following unpleasant state. After discontinuation of repeated exposure to addictive drugs, compensatory reactions develop that oppose the primary effects of the drug—the withdrawal symptoms. The reduction of the withdrawal symptoms would therefore represent negative reinforcement. The reduction of the unpleasant state of the withdrawal symptoms becomes the major drive in continued drug use. In a simplified view of the dopamine theory (Wise, 1978, 2008; Berridge and Robinson, 1998; Everitt and Robbins, 2005; Diana, 2011), the acute euphoric process obtained by binge-intoxication represents the activation of the dopaminergic system, while the negative component resulting from the withdrawal period is marked by the reduction of dopamine function (Tomkins and Sellers, 2001). The introduction of functional toxicity (Weiss and Koob, 2001), which is associated with the unpleasant withdrawal state powered by the recruitment of the stress neurotransmitter, CRF, further expanded the dopamine theory as it applies to addiction.
CRF, also known as corticotropin releasing hormone (CRH), has been shown to induce various behavioral changes related to adaptation to stress. Dysregulation of the CRF system at any point can lead to a variety of psychiatric disorders such as depression, obsessive compulsive disorder, post-traumatic stress disorder and SUDs (Cole et al., 1990; Sarnyai et al., 1992, 2001; Cador et al., 1993; Koob and Kreek, 2007; Koob and Le Moal, 2008a). Footshock-induced stress has been shown to be effective in inducing reinstatement of alcohol (Le et al., 1998, 2000; Gass and Olive, 2007; Richards et al., 2008), nicotine (Buczek et al., 1999), cocaine (Erb et al., 1996), opiate and psycostimulants (Lu et al., 2003) and heroin (Shaham et al., 1997) seeking. Specifically CRF has been associated with drug reinstatement (Shaham et al., 1997; Le et al., 2002; Liu and Weiss, 2002; Funk et al., 2006). CRF has also been shown to produce anxiety-like behaviors during withdrawal from chronic ethanol (Baldwin et al., 1991; Overstreet et al., 2004) and may be responsible for persistent vulnerability and eventual relapse.
The CRF system consists of four ligands: CRF, urocortin (UCN) (Vaughan et al., 1995) 1, 2, and 3, two G-protein-coupled receptors (GPCR), CRF-receptor 1 (CRF-R1) and CRF-receptor 2 (CRF-R2), as well as a secreted CRF binding protein (CRF-BP); see Table Table11 and (Bale and Vale, 2004) for CRF system review.
|Name||Type||Receptor binding||CNS expression||Peripheral expression||Involvement in stress response|
|CRF||ligand||CRF-R1 > CRF-R2||synthesized in PVN widely distributed||gut, skin, adrenal gland||HPA axis: induces ACTH release outside HPA axis: controls autonomic and behavioral responses|
|CRF-R1||receptor||–||CC, CB, MS, HIP, VTA, amygdala, pituitary||β cell pancreas||anxiogenic|
|CRF-R2||receptor||–||RN, LS, HY, CP||heart, GI, lung, skeletal muscle, vasculature||anxiogenic/anxiolytic|
|CRF-BP||binding protein||–||CC, HY, amygdala, VTA||Plasma, amniotic fluid, placenta, pituitary gland, liver||Periphery: neutralizes CRF CNS: undetermined|
|UCN 1||ligand||CRF-R1/CRF-R2||EW||GI, testis, cardiac myocytes, thymus, skin, spleen||Periphery: elevated in heart failure (Wright et al., 2009) CNS: modulate excitatory glutamatergic synaptic transmission (Liu et al., 2004)|
|UCN 2||ligand||CRF-R2||HY, brainstem, spinal cord||heart, blood cells, adrenal gland||central autonomic and appetitive control (Reyes et al., 2001) gender difference in depressive-like behavior (Chen et al., 2006)|
|UCN 3||ligand||CRF-R2||HY, amygdala||GI, pancreas||energy homeostasis (Li et al., 2007) anxiolytic-like effects (Valdez et al., 2003)|
CeA, central nucleus of the amygdala; CB, cerebellum; CC, cerebral cortex; CP, choroid plexus; EW, cell bodies of the Edinger Westphal nucleus; GI, gastrointestinal tract; HIP, hippocampus; HY, hypothalamus; LS, lateral septum; MS, medial septum; OLF, olfactory area; PVN, paraventricular nucleus of the hypothalamus; RN, raphe nuclei.
It was originally identified as a hypothalamic factor responsible for stimulating adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary (Guillemin and Rosenberg, 1955; Saffran et al., 1955) where it stimulates glucocorticoid synthesis and secretion form the adrenal cortex (Turnbull and Rivier, 1997). Its name was established thirty years before its biochemical identification in the 1980's (Vale et al., 1981) while its gene identifier in the National Center for Biotechnology Information (NCBI) is CRH. It is a 4.7-kilo-Dalton (kDa) peptide and consists of 41-amino acid residues. Neurosecretory neurons of the paraventricular nucleus (PVN) of the hypothalamus synthesize CRF (Meloni et al., 2005). CRF is then released into the afferent portal blood vessels to the anterior pituitary gland where it induces ACTH release in the systemic circulation. The hypothalamic-pituitary-adrenal (HPA) axis is regulated by negative feedback from glucocorticoids that activate glucocorticoid receptors specifically in the PVN and hippocampus. CRF is also expressed outside the HPA axis to control autonomic and behavioral responses to stressors (Palkovits et al., 1983; Swanson et al., 1983) including stress-induced reinstatement of drug seeking.
CRF mediates physiological stress responses by activating CRF-R1 and CRF-R2, which are distributed throughout the periphery and the brain (De Souza, 1995; Bale and Vale, 2004). It is believed that the binding of CRF to CRF-Rs is a two-step mechanism. The N-terminus of the receptor initially binds to the C-terminus of CRF, which initiates a rearrangement of the receptor (Grace et al., 2007). The CRF N-terminus contacts the other sites on the receptor to initiate cellular signaling (Vale et al., 1981; Rivier et al., 1984) and consequently activate the G-protein (Nielsen et al., 2000; Grace et al., 2004; Rijkers et al., 2004; Yamada et al., 2004; Hoare, 2005). The CRF system comprises other peptides with structural homology to CRF. UCN 1 shows 45% sequence identity with CRF and binds with high affinity to both CRF receptor subtypes (Perrin et al., 1995), whereas CRF binds with highest affinity to CRF-R1 (Vaughan et al., 1995; Burnett, 2005). UCN 2, also known as stresscopin related peptide, and UCN 3, also known as stresscopin bind specifically to CRF-R2 (Hsu and Hsueh, 2001; Lewis et al., 2001; Reyes et al., 2001).
CRF-R1 has 415 amino acid residues and it is expressed in the periphery and in the CNS (Chang et al., 1993; Chen et al., 1993; Vita et al., 1993; Potter et al., 1994; Tsai-Morris et al., 1996; Sanchez et al., 1999; Van Pett et al., 2000). Chronic stress mediated by activation of CRF-R1 by CRF has been associated with the development of anxiety disorders (Arborelius et al., 1999); CRF-R1 antagonists have been shown to reduce anxiety-like behaviors (Funk et al., 2007). Transgenic mice with deletion of CRF-R1 (CRF-R1 knock out (KO) mice) have reduced reaction to both stress and anxiety, for comprehensive review see (Bale and Vale, 2004). This anxiolytic effect, however may be attributed to the reduction in circulating glucocorticoids in preclinical models (Tronche et al., 1999). A conditional KO mouse line was generated to differentiate the behavioral from the neuroendocrine CRF-mediated CRF-R1 signaling pathways. The selective inactivation of the limbic structures, but not of the HPA system has shown that CRF-R1 modulates anxiety-like behaviors and it is independent of the HPA (Muller et al., 2003). Furthermore, CRF-R1 is thought to increase susceptibility to alcohol relapse behaviors (Hansson et al., 2006; Heilig and Koob, 2007). A recent study evaluated the role of CRF both within and outside the HPA has shown that CRF via CRF-R1 signaling may have opposite effects on stress-related alcohol consumption (Molander et al., 2012).
CRF-R2 has three variants: α,β, and γ. The α is comprised of 411 amino acid residues and the β is comprised of 413–418 amino acid residues. Both are found in the brain and periphery; however, CRF-R2β is predominantly found in the heart and vasculature (Lovenberg et al., 1995a,b; Kimura et al., 2002; Burnett, 2005). The γ variant is a smaller peptide containing only 397 amino acid residues, and is found only in the human brain (Kostich et al., 1998). The precise role of CRF-R2 in the regulation of the stress response is a subject of intense investigation. Genetic mouse model studies with deletion of CRF-R2 (CRF-R2 KO mice) have demonstrated that CRF activation of CRF-R2 can lead to either an increased or decreased response to stressors (Bale et al., 2000, 2002; Coste et al., 2000; Kishimoto et al., 2000).
The lack of specific antisera that support immunohistochemical experiments and the low resolution of ligand binding approaches have limited the studies to elucidate the CRF-Rs distribution and limit the analysis at the mRNA level. To overcome this impediment, a transgenic mouse that reports expression of CRF-R1 with green fluorescent protein (GFP) has been successfully generated providing a novel tool to investigate the role of CRF-R1 signaling in stress adaptation (Justice et al., 2008).
CRF-BP is a water-soluble, 37 kD protein and consists of 322 amino acid residues (Bale and Vale, 2004). It is a secreted glycoprotein, efficiently stored into secretory granules and released into the extracellular space through exocytosis (Blanco et al., 2011). It contains aspargine N-linked-type oligosaccharides that are critical for CRF-BP binding to CRF (Suda et al., 1989). Previous attempts to identify small molecule inhibitors of CRF-BP have produced limited success due in part to the high affinity (picomolar) of CRF binding to CRF-BP (Behan et al., 1995a) and also because CRF-BP full length (FL) is susceptible to autocatalytic proteolysis (Woods et al., 1999). The spontaneous proteolytic cleavage yields a larger N-terminal fragment of 27 kD, CRF-BP (27 kD), which retains the binding site for CRF and a smaller, 9.6 kD C-terminal fragment, CRF-BP (10 kD) (Woods et al., 1999) with no apparent physiological or pathological role. The unique cleavage site in CRF-BP (FL) has been identified between amino acid residues serine 234 and alanine 235. The generation of two fragments has made it extremely difficult to successfully purify sufficient quantities of CRF-BP (FL) to study the physiological properties of the native protein. CRF-BP is distributed in plasma, amniotic and synovial fluid, the placenta, the pituitary gland, the liver, and in several distinct brain regions, including the cerebral cortex, the hippocampus (Behan et al., 1995a), the amygdala (Herringa et al., 2004) and the VTA (Wang and Morales, 2008). In the periphery, circulating CRF-BP neutralizes the physiological actions of CRF (Kemp et al., 1998). Because of the high affinity with CRF, it is believed that CRF-BP plays a buffer role by reducing the amount of free CRF. In the brain, however, CRF-BP is mostly membrane-bound and expressed in different amounts in neurons and neuroglial cells (Behan et al., 1995b). Within neuronal cells, recent findings demonstrated that discrete subpopulations of VTA dopaminergic and γ-aminobutyric acid (GABAergic) neurons express CRF-BP (Wang and Morales, 2008). The physiological role of CRF-BP in the central nervous system (CNS) is still unclear. Additionally, theories suggest the possibility that CRF-BP may assist the clearance of CRF from the body and may also protect CRF from degradation (Seasholtz et al., 2002). Genetic mouse model studies with deletion of CRF-BP (CRF-BP KO mice) have shown there is an increase in anxiety-like behavior (Karolyi et al., 1999). Electrophysiology studies have shown that CRF signals through CRF-R2 to potentiate N-Methyl-D-aspartate (NMDA)-mediated excitatory postsynaptic currents (EPSCs) in the VTA (Ungless et al., 2003). Furthermore, using CRF (6–33), a peptide that competes with CRF at the CRF-BP binding site, but does not bind to CRF-R2, it was shown that it blocked CRF-induced potentiation of NMDAR-mediated EPSCs (Ungless et al., 2003). Taken together, these results suggest that CRF-BP possesses a diverse role in modulating the CRF-system. As described by in vitro and in vivo studies, purifying human CRF-BP (FL) in sufficient quantities for investigation has not been successful to date (Woods et al., 1997). There have not been any research tools available to characterize the role of CRF-BP in the CNS by expressing CRF-BP on the cell surface. Therefore, it has not been possible to determine whether CRF-BP participates specifically in the CRF-R2 signaling. A summary of the involvement of the CRF binding in addictive behavior is described in Table Table22.
|CRF-R1 antagonists||Attenuate stress-induced relapse to drug seeking and behavioral changes associated with withdrawal; small molecules and peptides are available for investigation|
|CRF-R2 antagonists||Regulation of the stress response and addictive behavior is unclear; small molecules and peptides are available for investigation|
|CRF-BP antagonists||Modulation of neuronal activity may be a target for both drugs of abuse and stress response; only peptides are available for investigation|
Addictive drugs have been shown to increase the concentration of dopamine in the NAcc. Furthermore, the increase of dopamine has been associated with the amplification of the hedonic impact of positive reinforcers (Fibiger, 1978; Berridge et al., 1989) and the development of addictive behaviors (Yokel and Wise, 1975; Bonci and Malenka, 1999; Wise, 2008). The NAcc receives input from the VTA and it is thought that this pathway may be responsible not only for the acute pleasure effect of drug intake, but also for the negative reinforcement and the effects of cues on drug-seeking behaviors (Koob and Nestler, 1997).
The VTA receives CRF projections mostly from the limbic forebrain and PVN of the hypothalamus (Rodaros et al., 2007) that form glutamatergic synapses and symmetric GABAergic synapses (Tagliaferro and Morales, 2008). The PVN is the site for CRF synthesis (Meloni et al., 2005) and the majority of asymmetric synapses (glutamatergic) are expressed in CRF- and dopaminergic-containing neurons. VTA dopaminergic neurons express CRF-R1 (Van Pett et al., 2000) and a more recent study has shown that the majority of VTA neurons expressing CRF-BP are dopaminergic (Wang and Morales, 2008).
The CRF system modulates dopaminergic neurons by activating CRF-R1 and CRF-R2; however, CRF is not only involved in the neuroexcitability of the dopaminergic system. It may also be responsible for modulating excitatory and inhibitory synaptic inputs since the VTA receive inputs from both CRF-glutamatergic- and CRF-GABAergic-containing neurons (Tagliaferro and Morales, 2008) and for review see Borgland et al. (2010).
CRF increases the firing rate of VTA dopaminergic neurons (Korotkova et al., 2006; Wanat et al., 2008) via CRF-R1, and involves the phospholipase C (PLC)–protein kinase C (PKC) signaling pathway with enhancement of Ih (hyperpolarization-activated inward current) (Wanat et al., 2008). CRF can also induce a transient slowly developing potentiation of NMDA-mediated synaptic transmission via CRF-R2 and activation of the PLC-PKC signaling pathway. CRF-R2-mediated potentiation has been shown to require the presence of CRF-BP (Ungless et al., 2003). The mechanism of action of CRF-R2 and CRF-BP is still under investigation as the research tools needed to study CRF-BP and antisera that specifically target CRF-R2 have not been available.
CRF appears to have both excitatory and inhibitory actions on the dopaminergic neurons in the VTA. Studies using cocaine and methamphetamine have shown that the excitatory effect of CRF on dopaminergic neurons involves fast events, for example action potential firing rate and NMDAR-mediated synaptic transmission, while the inhibitory effects of CRF involve slow forms of synaptic transmission that would result in long-term plasticity (Beckstead et al., 2009). Those observations demonstrated that CRF may have different actions on receptors that mediate the synaptic action on dopamine. This cellular mechanism may refine the role of stress by CRF actions on dopamine-mediated behaviors (Beckstead et al., 2009).
As it has been shown that potentiation of CRF-R2, but not CRF-R1, signaling requires the presence of CRF-BP (Ungless et al., 2003), it has been proposed that CRF-BP and CRF-R2 mediate longer-lasting forms of synaptic plasticity (Bonci and Malenka, 1999). Both behavioral sensitization and long-term potentiation (LTP) share many characteristics such as the involvement of NMDAR activation for the induction of LTP in VTA dopaminergic neurons (Bonci and Malenka, 1999; Ungless et al., 2001). As a consequence, it has been suggested that synaptic plasticity at excitatory synapses on VTA dopaminergic neurons may play a principal role in triggering behavioral change. Since NMDAR activation is required for the induction of LTP in VTA dopaminergic neurons, CRF-Rs activation may modulate longer-lasting forms of plasticity (Bonci and Malenka, 1999; Ungless et al., 2001; Bonci and Borgland, 2009).
Synaptic adaptations observed in remodeling of neuronal circuits in addictive drug studies have been shown to have implications in behavior and memory traits that characterize SUDs. The neuroplasticity underlying drug-induced sensitization has produced a growing body of evidence that suggests it may represent the molecular effect that is critical in modulating addictive behaviors and would contribute to stress-induced compulsive behaviors in addiction.
Axon terminals of CRF neurons synapse onto VTA neuronal dendrites (Tagliaferro and Morales, 2008) and it appears that stress affects the CRF release in this region (Wang et al., 2006). Electrophysiological studies have shown that CRF-BP is required for a slowly developing, transient potentiation of NMDAR-mediated synaptic transmission elicited by CRF via CRF-R2 specifically (Ungless et al., 2003). These results have been corroborated by behavioral studies that determined the effectiveness of stress in triggering glutamate and dopamine release in cocaine seeking of drug-experienced rats (Wang et al., 2007b). Using chronic cocaine preclinical models, the study has shown the positive reinforcement associated with CRF, specifically CRF/CRF-R2/CRF-BP interaction with the dopaminergic system. Those findings support additional research efforts to develop novel approaches that probe CRF-BP on the cell surface.
In conclusion, CRF increases VTA glutamatergic synaptic function, which may facilitate VTA burst firing or induction of synaptic plasticity that may result from repeated exposure to drugs of abuse. This process may produce long-term neuroadaptations that alter stress responses and enhance drug seeking. Electrophysiological studies combined with behavioral studies have proposed that previous experience with drugs of abuse may facilitate the ability of stress to drive drug seeking and, therefore, relapse. These results suggest that CRF may be important for drug-evoked synaptic plasticity in VTA dopaminergic neurons and may represent the molecular substrate that explains the anxiety and stress response during withdrawal from substances of abuse.
The amygdala is believed to be a pivotal brain region for emotional response and it is critical for providing affective salience to sensory information (Adolphs et al., 1994; LeDoux, 2003; Phelps and LeDoux, 2005). Negative affective responses have been studied in specific nuclei of the amygdala by studying the conditioned fear response (Davis, 1992a,b). The amygdala is widely connected to other limbic regions where it participates in integrating sensory and cognitive information (LeDoux, 1992, 1993). Experimental evidence strongly suggests drugs of abuse act on this system and can modify synaptic events especially during withdrawal. While the VTA has been associated with the reinforcing effects of ethanol (Gatto et al., 1994), the activation of the GABAergic system has been associated with alcohol's anxiolytic effect (Frye and Breese, 1982). In addition to the rewarding circuits of the shell of the NAcc, and brain regions activated by pharmacological stressor, such as yohimbine and footshock were found to be specific in the basolateral and central amygdalar nuclei, and the bed nucleus of the stria terminalis (BNST) (Funk et al., 2006). Preclinical studies demonstrated that exposure and withdrawal from ethanol induces functional and biochemical changes in the amygdala of rats, demonstrating that this circuit is involved in long-term increases in anxiety-like behavior following chronic ethanol exposure (Christian et al., 2012).
The amygdala mediates conditioned and unconditioned responses to aversive stimuli (Davis and Whalen, 2001) and it has been investigated using Pavlovian fear conditioning by pairing a conditioned stimulus with an aversive unconditioned stimulus. The re-exposure of the unconditioned stimulus elicits a conditioned fear response derived by the conditioned-unconditioned association (Pitts et al., 2009). The association signal takes place in the basolateral amygdala (BLA) and is then transmitted to the central nucleus of the amygdala (CeA) (McDonald, 1998; Maren, 1999; Davis and Shi, 2000; Pitkanen et al., 2000; Pare et al., 2004). This transmission process involves both positive and negative associations.
All components of the CRF system, CRF, CRF-Rs and CRF-BP are expressed in the amygdala (Potter et al., 1994). Furthermore, the amygdala is a major extrahypothalamic source of CRF-containing neurons (Palkovits et al., 1983; Van Pett et al., 2000). Both BLA and CeA nuclei play a role in the stress response (Richter et al., 1995; Merali et al., 1998; Koob and Heinrichs, 1999). Extensive studies have shown that the CRF system participates in memory consolidation that involves the BLA-CeA circuit (Roozendaal et al., 2002; Hubbard et al., 2007). It has been observed that CRF release in the amygdala is increased during acute withdrawal (Richter and Weiss, 1999); therefore, it has been hypothesized that CRF may modulate drug-evoked synaptic plasticity (Ungless et al., 2001, 2003) and for a recent review, see (Luscher and Malenka, 2011). The neuronal basis for negative reinforcement is less well-understood; however, more recent behavioral studies have shown that CRF is capable of potentiating excitatory synaptic currents via CRF-R1 in the CeA two weeks following withdrawal from cocaine (Pollandt et al., 2006).
A recent study has shown that CRF-R1 specifically possess a bidirectional role in anxiety (Refojo et al., 2011). While deletion of CRF-R1 in the mid brain dopaminergic neurons increases anxiety-like behaviors and reduces dopamine release in the prefrontal cortex, deletion of CRF-R1 in the forebrain glutamanergic neuronal network reduces anxiety and disrupts transmission in the amygdala and hippocampus (Refojo et al., 2011).
The role of CRF was also evaluated extensively in voluntary ethanol consumption using gene expression and genetic variation in preclinical models see (Bjork et al., 2010) for extensive review. In ethanol-exposed animals, ethanol intake was reduced by administration of CRF-R1 antagonist, and tested using pharmacological interventions that reduce anxiety-like behaviors (Logrip et al., 2011; Zorrilla and Koob, 2012). The reduction of ethanol intake was also observed in transgenic mice with deletion of CRF-R1 (CRF-R1 KO) (Chu et al., 2007). CRF-R1 antagonists reduce drug withdrawal-associated anxiety and attenuate the negative reinforcing effects of ethanol associated with prolonged ethanol exposure (Ghitza et al., 2006; Marinelli et al., 2007; Li et al., 2007; Koob and Le Moal, 2008b; Richards et al., 2008). CRF-R1 inhibitors have shown to attenuate stress-induced relapse to cocaine and heroin in trained animals (Shaham et al., 1998) and to reduce stress-induced reinstatement and stress-induced reactivation of conditioned place preference in many addictive drugs (Koob and Zorrilla, 2010).
Among the extrahypothalamic structures that contain CRF expressing neurons there is the “extended amygdala.” The extended amygdala is comprised by the BNST, the central medial amygdala (CeA), the sublenticular sustantia innominata and a transition zone forming the posterior part of the NAcc (Heimer and Alheid, 1991). It represents the brain circuit involved in processing the aversive stimuli produced by ethanol withdrawal (Koob and Le Moal, 2001), in which the GABA system has been altered and the CRF system in the adjacent CeA has been shown to be activated (Roberts et al., 1996). Those observations indicate that GABAergic activity within interneurons of the extended amygdala may play a prominent role in the chronic negative emotion-like state of motivational significance for drug seeking in alcohol dependence (Koob and Le Moal, 2001; Koob, 2003, 2009a,b). In addition, an in situ hybridization study has shown that recruitment of CRF-R1 signaling, in the components of the extended amygdala, may be responsible of driving the excessive voluntary alcohol intake and may be linked to increase stress activity (Hansson et al., 2007).
The BNST (as well as distinct regions of the CeA) has been associated with stress and anxiety (Walker and Davis, 2008) and is involved specifically with CRF signaling (Davis et al., 1997). The CeA and BNST have direct projections to many brain regions that have been studied to elucidate the symptoms of fear or anxiety (Davis, 1992b). The BNST has been identified as a possible regulator of VTA dopaminergic neuron firing (Georges and Aston-Jones, 2002) and consequently involved in the regulation of acute actions of alcohol, nicotine, and cocaine (Watkins et al., 1999; Carboni et al., 2000; Eiler et al., 2003).
The BNST possesses an extensive network of dopaminergic fibers (Fudge and Emiliano, 2003) and is connected to the reward pathway by extensive projections to the VTA, thus influencing the excitatory input through both NMDA and non-NMDA receptors (Georges and Aston-Jones, 2001, 2002). This dopaminergic excitatory transmission in the VTA requires the presence of CRF (Kash et al., 2008). Acute cocaine administration has been shown to induce dopamine signaling through a specific CRF-R1-dependent enhancement of NMDA excitatory transmission (Kash et al., 2008). This mechanism was described as a short-term form of plasticity in the BNST, which may be responsible for the acute effects of addictive drugs (Kash et al., 2008). These findings suggested that glutamatergic neurotransmission in BNST may be functionally involved with acute reinforcing actions of drug of abuse (Walker and Davis, 2008).
The basolateral nucleus of the amygdala (BLA) is critically implicated in emotional learning (LeDoux, 2000), and in reward (Balleine and Killcross, 2006; Tye et al., 2008). Neurons from the BLA project directly to the CeA as well as to the BNST. The BLA is mostly composed by glutamatergic pyramidal neurons and provides the main excitatory input to the CeA and other limbic and cortical structures (Sah et al., 2003); however, the excitatory transmission is believed to be modulated by the relatively small number of GABAergic interneurons found there (Washburn and Moises, 1992). GABAergic interneurons have been identified as regulators of stress and anxiety (Silberman et al., 2009).
CRF is present abundantly in the BLA, in addition to CRF-R1 and CRF-BP, (Sakanaka et al., 1986; Potter et al., 1992; Van Pett et al., 2000); however, the effects of CRF in the BLA have been studied far less than the other nuclei of the amygdala. The BLA has been shown to be a critical nucleus for the consolidation of fear and memory and, therefore, is a possible target for dampening emotional memories. It has been shown that intra BLA infusions of CRF increase anxiety-like behaviors (anorexia and grooming) that are blocked by the administration of a CRF-R1 antagonist (Jochman et al., 2005). Another BLA microinfusion study showed that CRF-R1 activates fear memory consolidation and that this effect is blocked by administration of another CRF-R1 antagonist. The fear memory consolidation process seems specifically regulated by the CRF-R1 activation since CRF-R2 antagonist in the BLA disrupted neither the contextual fear conditioning nor performance of contextual freezing in the drug-free conditioned fear test (Hubbard et al., 2007). BLA CRF-R1 activation has been described as induced synaptic plasticity, and demonstrating that BLA CRF-R1 activation can be pharmacologically blocked by small molecules, the possibility to compromise the consolidation of fear memory suggests a potential therapeutic opportunity to ease the development of intense emotional memories.
The CeA has been identified as locus for both acute positive reinforcement of ethanol self-administration and for the negative reinforcement associated with ethanol withdrawal (Baldwin et al., 1991; Heinrichs et al., 1992, 1995; Koob and Le Moal, 1997, 2001; Zorrilla et al., 2001). The CeA has also been identified as a critical locus for reversing many behavioral effects associated with ethanol intoxication (Hyytia and Koob, 1995).
In the CeA, most neurons are GABAergic (Sun and Cassell, 1993), and CRF is highly co-expressed with GABAergic neurons (Veinante et al., 1997; Day et al., 1999). The CeA abundantly expresses CRF, CRF-R1 and CRF-BP (Sakanaka et al., 1986; Potter et al., 1992; Van Pett et al., 2000). Moreover, in the CeA the action of CRF and ethanol has been shown to increase GABA release (Nie et al., 2004) and the amount of CRF release is increased in preclinical models of ethanol dependence (Merlo Pich et al., 1995). Protein kinase C epsilon (PKCε) has been shown to modulate CRF-R1 signaling in the CeA (Choi et al., 2002) and transgenic mice with deletion of PKCε (PKCε KO mice) have shown reduced anxiety-like behaviors (Hodge et al., 2002). Electrophysiological studies have shown that ethanol-induced GABA release in the amygdala is regulated by CRF-R1 (Nie et al., 2004) and that ethanol-stimulated vesicular GABA release depends on PKCε models (Bajo et al., 2008). PKCε signaling pathway in the CeA is activated by CRF-R1 activation and modulates GABAergic neurotransmission that may contribute to the anxiogenic effects of ethanol (Smith et al., 1998; Timpl et al., 1998). This functional link between ethanol, CRF and PKCε that modulates GABAergic neurotransmission in the CeA may contribute to the dysregulation of emotional behaviors that regulate acute positive reinforcement of ethanol consumption and the negative reinforcement produced by ethanol withdrawal.
It has been shown that there is a critical difference between CRF effects in low/moderate ethanol-exposed animals (binge-like ethanol consumption) and ethanol-dependent animals (chronic-like ethanol exposure). While binge-like ethanol (Lowery-Gionta et al., 2012) may cause transient perturbations of the CRF system which may be able to return to its homeostatic state, the chronic-like ethanol exposure (Roberto et al., 2003, 2004) may be responsible for the CRF neuroadaptation that would influence the allostatic state. An allostatic state is defined as a state of chronic deviation of the regulatory network from their normal process and the establishment of a different set point of “apparent stability” (Koob and Le Moal, 2001). This chronic deviation of reward set point is critically altered during drug withdrawal and may contribute to subsequent neuroadaptation that produces vulnerability to addiction and relapses (Koob and Le Moal, 2001). Acute stress does not increase the mRNA expression of any components of the CRF system in the CeA (Herringa et al., 2004), however, in the CeA of animals exposed to ethanol, there was a significant increase in CRF mRNA expression (Lack et al., 2005) as well as in ethanol-dependent animals during withdrawal (Sommer et al., 2008).
The recruitment of CRF in the CeA during early drinking episodes, before dependence, may initiate neuroplastic changes in the system that may become more intense with additional ethanol exposures (Lowery-Gionta et al., 2012). It has been proposed that this CRF-dependent change contributes to the transition from binge-drinking to ethanol dependence (Lowery-Gionta et al., 2012). The authors also found that ethanol enhances GABAergic transmission in the amygdala at both pre- and post-synaptic sites in ethanol naïve animals, while binge ethanol consumption blunts the CRF-mediated GABAergic transmission (Lowery-Gionta et al., 2012). This study revealed that drinking reduced the effect CRF has on GABAergic transmission. In contrast, others have found that animals dependent on ethanol showed enhanced GABAergic transmission in the CeA (Roberto et al., 2004).
CRF and norepinephrine have been shown to increase GABAergic activity measured by GABAA inhibitory postsynaptic potential (IPSCs) in whole-cell recording from the CeA. This effect was blocked by CRF-R1 antagonists and blocked in CRF-R1 knockout mice (Nie et al., 2004; Kash and Winder, 2006). The augmented GABA release produced by ethanol in the CeA in dependent animals was observed both in electrophysiological and in vivo microdialysis experiments (Roberto et al., 2003). Later studies in ethanol-dependent rats corroborated that CRF-alcohol interaction on GABAergic transmission in the CeA is more pronounced during alcohol dependence (Roberto et al., 2004).
This review has summarized the multiple mechanisms that underlie persistent changes in synaptic efficacy following administration of addictive drugs. It is evident that the CRF system significantly facilitates the induction and maintenance of plasticity in the VTA and amygdala, with resulting enhancement of glutamate-mediated excitation and reduction of GABA-mediated inhibition, thus contributing to the molecular basis of drug addiction.
Neuroplasticity in brain reward circuitry following a history of ethanol dependence has been shown (Hansson et al., 2008). Experimental data illustrated in this review support the hypothesis that stress induces plasticity within the VTA and amygdala nuclei and may participate in the development of a chronic anxiety state that could lead to the development of SUDs. These changes in the limbic neuronal network may represent the trigger that may lead to loss of control of drug use. Addictive drugs have been shown to induce behavioral sensitization and there is a large body of literature that evaluates the role of stress and addictive behaviors. Studies of long-term neuroadaptation in alcohol addiction have shown that brain stress and fear systems become activated (Heilig et al., 2010); however, there is still much to be elucidated pertaining to drugs' actions on the CRF system, both in regard to synaptic plasticity and behavioral responses. Several blood–brain barrier-penetrating CRF-R1 antagonists have been developed, however while some compounds have shown efficacy in animal models to treat alcoholism (Gehlert et al., 2007, 2012), CRF-R1 antagonists have still not succeeded in clinical trials (Koob and Zorrilla, 2012).
Preventing all exposure to substances of abuse is almost impossible, as many psychoactive substances (alcohol, nicotine, caffeine, and prescription medications) are generally accepted in our society. There are many medications that are FDA approved or used off-label for alcohol dependence that focus on the treatment of symptom reduction (disulfuram, naltrexone), assistance with withdrawal (benzodiazepines, valporic acid, varenicline), and relapse prevention (acamprosate, ondansetron, baclofen, topiramate, varenicline, methadone) and others FDA approved medications for other indications are at the preclinical stage (mifepristone) (Simms et al., 2011), however, the recidivism in drug abuse is still a major problem for SUDs. Although different classes of substances of abuse have different mechanisms of action, repeated drug use leads to stimulation of the HPA axis and the abrupt cessation of chronic drug use increases activation of CRF. Medications that modulate stress responses may offer a novel pharmacotherapeutic approach for SUDs. Regulating stress outcomes by acting on the CRF system may offer the possibility to develop that novel therapeutic directed to diminish the effect of CRF in synaptic transmissions. By easing the stress-induced drug seeking, it may be possible to reduce relapse and facilitate the formation of memories with less deleterious behavioral consequences.
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.
We thank J. Simms, S. Srinivasan and L. Daitch for their contribution to the editing of the manuscript. This work was supported by funding from the State of California Medical Research on Alcohol & Substance Abuse through UCSF to Selena E. Bartlett, the National Institutes of Health: 1R21DA029966-01 and NIH Fast Track award to screen the MLSMR collection to Selena E. Bartlett, UCSF School of Pharmacy (Dean's Office and Clinical Pharmacy) and the School of Medicine (Clinical Pharmacology and Experimental Therapeutics) to Carolina L. Haass-Koffler.
Cereb. Cortex (2007) 17 (12): 2796-2804. doi: 10.1093/cercor/bhm008 First published online: February 24, 2007
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Although the medial prefrontal cortex (mpFC) appears to constrain stress responses, indirect evidences suggest that it might determine the stress response of the mesoaccumbens dopamine (DA) system. To test this hypothesis, we first evaluated the dynamics of norepinephrine (NE) and DA release in the mpFC and of DA release in the nucleus accumbens (NAc) of acutely stressed rats. Then, we tested the effects of selective depletion of NE or DA in the mpFC (by local 6-hydroxydopamine infusion following desipramine or 1-[2[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine(GBR 12909) on stress-induced changes in mesoaccumbens DA release.
Rats experiencing restraint stress for 240 min showed an initial, short-lived increase of NE outflow in the mpFC and of DA in the NAc. These responses were followed by a sustained increase of DA in the mpFC and by a decrease to below resting levels of DA in the NAc.
Moreover, selective prefrontal NE depletion eliminated the increase of NE in the mpFC and of DA in the NAc, and selective depletion of mesocortical DA eliminated the enhancement of mpFC DA as well as the inhibition of mesoaccumbens DA, without affecting basal catecholamines outflow.
These results demonstrate that the opposing influences of mpFC NE and DA determine mesoaccumbens DA response to stress and suggest that alterations of this mechanism may be responsible for some major psychopathological outcomes of stress.