Stress and Addiction

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

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

The Darkness Within Individual Differences in Stress (2015), George F. Koob, Ph.D.

The Darkness Within Individual Differences in Stress

Wednesday, April 01, 2015

By: George F. Koob, Ph.D.

Editor’s Note: Numerous factors make us react to situations differently: age, gender, education, relationships, socioeconomic status, environment, cultural background, life experience. But as our author describes, biological bases, such as the way genetics and neurochemicals affect our brains, are providing insight into addiction, posttraumatic stress disorder, and other stresses that he calls “an intimate part of modern life.”

S tress is everywhere. It is an intimate part of modern life. But what is stress? How does the brain process the feeling as a “stress system”? What chemicals in our brains mediate the stress response, and, most important, can we control it? Moreover, what conveys individual differences in stress responsivity that leave some of us vulnerable to stress disorders and others resilient? When does stress go rogue and produce psychopathology? And why do I think of it as the “dark side” of reward pathways in the brain.

My hypotheses are that individual differences in stress vulnerability and resilience are key determinants of the development of posttraumatic stress disorder (PTSD) and addiction, and these differences derive from the neurocircuitry of our emotional dark side. I’ll take you through this neurocircuitry to explain what I mean. 

What is Stress?

Stress can be classically defined as “the nonspecific (common) result of any demand upon the body”1 or, from a more psychological perspective, “anything which causes an alteration of psychological homeostatic processes.”2 Historically, the physiological response that is most associated with a state of stress is an elevation of chemicals called glucocorticoids that help control inflammation. Glucocorticoids are derived from the adrenal cortex, a gland situated above the kidneys, and glucocorticoid elevations were thought to be controlled by the brain’s hypothalamus, a region that is associated with emotion. Maintaining psychological homeostasis, therefore, involves responses among the nervous, endocrine, and immune systems. This nexus is referred to as the hypothalamic-pituitary-adrenal axis (HPA) .

Efforts to identify processes involved in disrupting psychological homeostasis began while I was a staff scientist at the Arthur Vining Davis Center for Behavioral Neurobiology at the Salk Institute in California. My colleagues Wylie Vale, Catherine Rivier, Jean Rivier, and Joachim Spiess first demonstrated that a peptide called corticotropin-releasing factor (CRF) initiates the HPA axis’s neuroendocrine stress response. Research showed that CRF emanated from a part of the hypothalamus called the paraventricular nucleus, which is the primary controller of the hypothalamic-pituitary-adrenal axis. When the hypothalamus releases CRF, it travels through blood vessels to the pituitary gland, located at the base of the brain. There, CRF binds to receptors located in the anterior part of this gland to release adrenocorticotropic hormone (ACTH) into the blood stream.3

ACTH in turn travels to the cortex of the adrenal gland to release glucocorticoids. Glucocorticoids, in turn, synthesize glucose to increase energy used by the brain, and glucocorticoids also decrease immune function by blocking “proinflammatory” proteins that ordinarily produce inflammation. Together these responses facilitate the body’s mobilization in response to acute stressors. Indeed, acute and chronic glucocorticoid responses differentially affect brain function, with acute high-dose glucocortoids imparting a protective effect. 4

Fight or Flight?

When faced with stressors, what determines whether we fight or flee? The human brain’s “extended amygdala” processes fear, threats, and anxiety (which cause fight or flight responses in animals)5,6 and encodes negative emotional states. Located in the lower area of the brain called the basal forebrain, the extended amygdala is composed of several parts, including the amygdala and nucleus accumbens. 7 This system receives signals from parts of the brain that are involved in emotion, including the hypothalamus and, most important for this examination, the prefrontal cortex. Extended amygdala neurons send axons or connections heavily to the hypothalamus and other midbrain structures that are involved in the expression of emotional responses.7,8

In psychopathology, dysregulation of the extended amygdala has been considered important in disorders related to stress and negative emotional states. These disorders include PTSD, general anxiety disorder, phobias, affective disorders, and addiction.9,10 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, and avoidance of open areas, all of which are typical responses to an aversive stimulus and are mediated in part by the extended amygdala.

The Neurochemical Mediators

Why then do individual responses to stress differ? Two important neurochemical systems are involved and help answer this question. The first one is CRF, the neurochemical system mentioned above. It turned out CRF is also a major component of the extended amygdala and works to effect behavioral changes.

While the glucocorticoid response mobilizes the body for physiological responses to stressors, CRF mobilizes the body’s behavioral response to stressors via brain circuits outside the hypothalamus. One of my first eureka moments was when my laboratory helped demonstrate initially that CRF mediates not only physiological and hormonal responses to stressors but also behavioral responses.

In our first study, I injected the newly discovered CRF peptide into the brain in rats and observed very peculiar behavioral hyperactivity. The rats climbed all over the wire-mesh testing cages, including the walls. I called Wylie Vale over to observe the animals because they seemed to be levitating.  We subsequently showed that injecting CRF into the rats’ brains produced a pronounced hyperarousal in a familiar environment but a pronounced freezing-like response in a novel stressful environment.11 Subsequent work showed that the extended amygdala mediates such responses to CRF and fear and anxiety in general. When agents were used to block CRF receptors from binding CRF, anti-stress effects occurred, confirming that the release of naturally produced CRF is central in behavioral responses to stressors.12 Equally intriguing, in chronic prolonged stress, glucocorticoids stimulate CRF production in the amygdala while inhibiting it in the hypothalamus, suggesting a means of protecting the body from high chronic exposure to glucocorticoids by shutting off the HPA axis but driving the extrahypothalamic CRF stress system.

The other key neurotransmitter system involved in individual differences in stress responsiveness is called the dynorphin-kappa opioid system (also located in the extended amygdala). This system is implicated in effecting negative emotional states by producing aversive dysphoric-like effects in animals and humans.13 Dysphoria is a negative mood state, the opposite of euphoria. Dynorphins are widely distributed in the central nervous system.14 They have a role in regulating a host of functions, including neuroendocrine and motor activity, pain, temperature, cardiovascular function, respiration, feeding behavior, and stress responsivity.15

In addition to these two neurochemical systems, we now know that other neurochemical systems interact with the extended amygdala to mediate behavioral responses to stressors. They include norepinephrine, vasopressin, hypocretin (orexin), substance P, and proinflammatory cytokines. Conversely, some neurochemical systems act in opposition to the brain stress systems. Among these are neuropeptide Y, nociceptin, and endocannabinoids. A combination of these chemical systems sets the tone for the modulation of emotional expression, particularly negative emotional states, via the extended amygdala.16

Psychopathology and Stress Systems

How are stress systems involved in PTSD? PTSD is characterized by extreme hyperarousal and hyperstress responsiveness. These states contribute greatly to the classic PTSD symptom clusters of re-experiencing, avoidance, and arousal. Perhaps more insidious, about 40 percent of people who experience PTSD ultimately develop drug and alcohol use disorders. Data suggest that the prevalence of an alcohol use disorder in people with PTSD may be as high as 30 percent.17 The major model of PTSD neurocircuitry evolved from early animal work on fear circuits,18 which suggested that brain stress systems are profoundly activated in the extended amygdala.

PTSD patients exhibit abnormally high glucocorticoid receptor sensitivity. This hypersensitivity results in excessive suppression of the HPA axis through corticosteroid negative feedback.19 Research has found that military participants who developed high levels of PTSD symptoms after deployment tended to be those who had significantly higher glucocorticoid receptor expression levels before deployment.20 Another key preclinical study showed that strong activation of CRF receptor signaling in animal models can induce severe anxiety-like and startle hyperreactivity that corresponds  to the severe anxiety and startle reactivity seen in patients with PTSD.21 Research also has demonstrated that patients with severe PTSD exhibit overly active brain CRF neurotransmission, measured by increases in CRF in their cerebrospinal fluid.22

While data on PTSD and the dynorphin-kappa system are limited, significant data suggest that brain kappa-opioid receptors play an important role in mediating stress-like responses and encoding the aversive effects of stress.13 An exciting recent imaging study with a kappa-opioid tracer showed decreased kappa-opioid binding in the brain in PTSD patients. This finding suggests increased dynorphin release in patients who are clinically diagnosed with PTSD.23

From a neurocircuitry perspective, functional imaging studies of patients with PTSD show that the amygdala is hyperactive while the ventromedial prefrontal cortex (PFC) and inferior frontal gyrus area show reduced activity.24 These findings suggest that the ventromedial PFC no longer inhibits the amygdala. This loss of inhibition in turn drives increased responses to fear, greater attention to threatening stimuli, delayed or decreased extinction of traumatic memories, and emotional dysregulation.25

One attractive hypothesis for the functional neurocircuitry changes that occur in PTSD suggests a brain-state shift from mild stress (in which the PFC inhibits the amygdala) to extreme stress (in which the PFC goes offline and the amygdala dominates; see figure 1).26 Under this paradigm (rubric means “a standard of performance for a defined population”), relative dominance by the cerebral cortex conveys resilience, and relative dominance by the amygdala conveys vulnerability.26 Delving further into the effects of prefrontal control, two related studies showed that ventromedial PFC activation correlates with the extinction of fear, whereas amygdala activation by the dorsal anterior cingulate cortex (ACC) correlates with a failure to eliminate fear.27,28
Figure 1. Common neurocircuitry in addiction and posttraumatic stress disorder (PTSD) with a focus of prefrontal cortex (PFC) control over the extended amygdala. The medial PFC inhibits activity in the extended amygdala, where key stress neurotransmitters mediate behavioral responses to stressors and negative emotional states. Key neurotransmitters include corticotropin-releasing factor (CRF) and dynorphin but also other stress and antistress modulators. Notice a significant overlap in the symptoms of PTSD and the withdrawal/negative affect stage of the addiction cycle.

The Paradoxical ‘Darkness Within’

I often tell people that I spent the first fifteen years of my career studying why we feel good and the most recent fifteen years studying why we feel bad. However, these two emotional states are intimately linked, which raises the seemingly contradictory possibility that excessive activation of the reward system can lead to stress-like states that, in their severest form, resemble PTSD. So how did I get to the “dark side”? Well, by first studying the “light side,” or how drugs produce their rewarding effects.

My research team and others hypothesized that addiction involves three stages that incorporate separate but overlapping neurocircuits and relevant neurotransmitter systems: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation or “craving.”29,30 The binge/intoxication stage involves the facilitation of incentive salience (the linking of previously neutral stimuli in the environment to rewards to give those stimuli incentive properties), mediated largely by neurocircuitry in the basal ganglia. The focus is on activation of the “reward” neurotransmitters dopamine and opioid peptides that bind to mu-opioid receptors in the brain. Early work in the addiction field showed that the nucleus accumbens was a key part of this neurocircuitry that mediates the rewarding properties of abused drugs.

Franco Vaccarino and I showed that we could block heroin self-administration when we injected minute amounts of methylnaloxonium, which blocks opioid receptors, into animals’ nucleus accumbens.31 Subsequently, several classic human imaging studies showed that intoxicating doses of alcohol result in the release of dopamine and opioid peptides in the nucleus accumbens.32,33 We now know that activation of the nucleus accumbens leads to the recruitment of basal ganglia circuits that engage the formation and strengthening of habits. This process is hypothesized to reflect the beginning of compulsive-like responding for drugs—in other words, addiction.

An experiment that turned out exactly the opposite of what I had predicted is the second reason I landed on addiction’s dark side. Tamara Wall, Floyd Bloom, and I set out to identify which regions of the brain mediate physical withdrawal from opiates. We began by training opiate-dependent rats to work for food. Then we disrupted their food-seeking behavior by injecting them with naloxone. This drug precipitated withdrawal, producing a malaise- and dysphoric-like state; as a result, the rats stopped pressing the lever. Thus far, we had successfully replicated original findings.34 We then  set out to inject methylnaloxonium, a drug that blocks opioid receptors in brain areas previously implicated in physical withdrawal from opiates.  We injected this drug because it was a naloxone analog that would spread less in the brain and precipitate “local” withdrawal as measured by a decrease in lever pressing for food.

We speculated that the most sensitive brain areas to produce a decrease in lever pressing would be the periaqueductal gray and medial thalamus because they had been shown to mediate physical withdrawal from opiates. However, injections into the periaqueductal gray and medial thalamus were ineffective in decreasing lever pressing for food. Instead, injections into the nucleus accumbens proved effective—so effective that we had to drop the dose. Even at a very low dose, we saw some modest effect in decreasing lever pressing for food.35 It then dawned on me that the same brain region responsible for making you feel good also made you feel bad when you became dependent (addicted). This epiphany led me to devote the rest of my career to trying to understand exactly how such opposite reactions that occur during withdrawal, termed opponent processes, are mediated.

This observation led me to a completely new conceptualization of the withdrawal/negative affect stage of addiction. I concluded that this stage is characterized not only by drug-induced specific “physical withdrawal” but also common drug-induced “motivational” withdrawal, characterized by dysphoria, malaise, irritability, sleep disturbances, and hypersensitivity to pain. (These symptoms are virtually identical to the hyperarousal/stress symptoms seen in PTSD; see figure 1).  

Two processes were subsequently hypothesized to form the neurobiological basis for the withdrawal/negative affect stage. One is the loss of function in the reward systems in the medial part of the nucleus accumbens of the extended amygdala. This reward system loss is mediated by a loss of function in dopamine systems. The other process is the recruitment of brain stress systems in other parts of the extended amygdala (notably, the central nucleus of the amygdala), including recruitment of the neurochemical systems CRF and dynorphin.36,37 The combination of decreases in reward neurotransmitter function and recruitment of brain stress systems provides a powerful motivation for reengaging in drug taking and drug seeking.

Yet another breakthrough came when my laboratory first realized the dramatic role of CRF in compulsive alcohol seeking, via the amelioration of anxiety-like responses when a CRF receptor antagonist or receptor blocker was used to block the anxiety-like responses of alcohol withdrawal.38 Subsequently, we showed that acute alcohol withdrawal activates CRF systems in the central nucleus of the amygdala.39 Moreover, in animals we found that site-specific injections of CRF receptor antagonists into the central nucleus of the amygdala or systemic injections of small-molecule CRF antagonists reduced the animals’ anxiety-like behavior and excessive self-administration of addictive substances during acute withdrawal.12,40 Perhaps equally compelling, Leandro Vendruscolo and I recently showed that a glucocortoid receptor antagonist could also block the excessive drinking during acute alcohol withdrawal, linking sensitization of the CRF system in the amygdala to chronic activation of the HPA glucocorticoid response. 41

But how is excessive activation of the reward system linked to activation of the brain stress systems? Seminal work by Bill Carlezon and Eric Nestler showed that the activation of d opamine receptors that are plentiful in the shell of the nucleus accumbens stimulates a cascade of events that ultimately lead to changes in the rate of DNA transcription initiation and alterations in gene expression. Ultimately, the most notable alteration is activation of dynorphin systems. This dynorphin system activation then feeds back to decrease dopamine release.37 Recent evidence from my laboratory and that of Brendan Walker suggests that the dynorphin-kappa opioid system also mediates compulsive-like drug responses (to methamphetamine, heroin, nicotine, and alcohol); this response is observed in rat models during the transition to addiction. Here, a small-molecule kappa-opioid receptor antagonist selectively blocked the animals’ development of compulsive drug self-administration.42-45 Given that the activation of kappa receptors produces profound dysphoric effects, this plasticity within the extended amygdala may also contribute to the dysphoric syndrome associated with drug withdrawal that is thought to drive the compulsive responses mediated by negative reinforcement.46

Yet another pleasant surprise was the realization that the preoccupation/anticipation, or “craving,” stage in alcoholism mediates the dysregulation of executive control via prefrontal cortex circuits. Importantly, these circuits can become a focal point for individual differences in vulnerability and resilience. Many researchers have conceptualized two generally opposing systems, a “Go” system and a “Stop” system, where the Go system engages habitual and emotional responses and the Stop system brakes habitual and emotional responses. The Go system circuit consists of the anterior cingulate cortex and dorsolateral PFC, and it engages habit formation via the basal ganglia. The Stop system circuit consists of the ventromedial PFC and ventral anterior cingulate cortex and inhibits basal ganglia habit formation, as well as the extended amygdala stress system. People with drug or alcohol addiction experience disruptions of decision making, impairments in the maintenance of spatial information, impairments in behavioral inhibition, and enhanced stress responsivity, all of which can drive craving. More important, this Stop system controls the “dark side” of addiction and the stress reactivity observed in PTSD.

This realization was brought home to me when my colleague Olivier George and I showed that, even in rats that simply engaged in the equivalent of binge drinking, there was a disconnection of the frontal cortex’s control over the amygdala but not nucleus accumbens.47 These results suggest that early in excessive alcohol consumption, a disconnect occurs in the pathway between the PFC and the central nucleus of the amygdala, and this disconnect may be key to impaired executive control over emotional behavior.

Evidence for a Genetic/Epigenetic Mechanism

I suspect that the neurocircuitry focus on the frontal cortex and amygdala in the development of PTSD and addiction will reveal targets for individual differences in vulnerability and resilience. Human imaging studies have established that reduced functioning of the ventromedial PFC and anterior cingulate cortex and increased functioning of the amygdala are reliable findings in PTSD.26. Similarly, drug addiction also has been associated with general reduced function of the ventromedial PFC.48 So what is the contribution of the ventralmedial PFC and anterior cingulate cortex in stress and negative emotional states associated with craving, particularly given what we already know in PTSD? Considering the high co-occurrence of substance abuse and PTSD and the key role of the PFC in controlling the stress systems, the dysregulation of specific subregions of the PFC may be involved in both disorders.  

Converging evidence in humans suggests major individual differences in the response of the extended amygdala to emotional stimuli, particularly those considered stressful, and in vulnerability to PTSD and addiction. Research has demonstrated that the central nucleus of the amygdala (the dorsal amygdala in humans) is involved in the conscious processing of fearful faces in healthy volunteers and, more important, that individual differences in trait anxiety predicted the response of a key input to the central nucleus of the amygdala, the basolateral amygdala, to unconsciously processed fearful faces.49 Moreover, a landmark study that used positron emission tomography showed that the amygdala is activated in cocaine-addicted individuals during drug craving but not during exposure to non-drug-related cues.50

Similarly, changes in frontal cortex function can convey individual differences in vulnerability and resilience. In one prospective study that was conducted following the 9.0 Tohoku earthquake in Japan in 2011, participants who had higher gray matter volume in the right ventral anterior cingulate cortex were less likely to have developed PTSD-like symptoms.51 The degree of improvement in symptoms after cognitive behavior therapy was positively correlated with increases in anterior cingulate cortex activation.52 In contrast, other studies have shown that people with PTSD and their high-risk twins show greater resting brain metabolic activity in the dorsal anterior cingulate cortex compared with trauma-exposed individuals without PTSD, suggesting that increased dorsal anterior cingulate cortex activity may be a risk factor for developing PTSD.53

But what molecular neurobiological changes drive these circuit changes? Genetic studies have shown that 30 to 72 percent of the vulnerability to PTSD and 55 percent of the vulnerability to alcoholism can be attributed to heritability. Most would argue that the genetic influences of both disorders stem from multiple genes, and the candidate-gene approach has not yet identified major genetic variants that convey vulnerability to PTSD. However, in two scholarly reviews, at least seventeen gene variants were associated with PTSD and many others with alcoholism.26 Overlapping genes that have been identified in both disorders include gamma-aminobutyric acid, dopamine, norepinephrine, serotonin, CRF, neuropeptide Y, and neurotrophic factors, all of which are relevant to the present hypothesis. 

From an epigenetic perspective, some genes may be expressed only under conditions of trauma or stress, and these environmental challenges can modify genetic expression via DNA methylation or acetylation. Both PTSD and alcoholism show epigenetic changes that suggest an increased regulation in genes related to the stress system.54,55 For PTSD, one gene that has been implicated in epigenetic modulation is SLC6A4, which regulates synaptic serotonin reuptake and appears to have a central role in protecting individuals who experience traumatic events from developing PTSD via high methylation activity.56 For alcoholism, histone deacetylase (HDAC) has been implicated in an epigenetic modulation. This gene is involved in the activity-dependent regulation of brain-derived neurotrophic factor (BDNF) expression in neurons. Alcohol-preferring rats with innate higher anxiety-like responses showed higher HDAC activity in the central nucleus of the amygdala. Knockdown of a specific HDAC called HDAC2 in the central nucleus of the amygdala increased BDNF activity and reduced anxiety-like behavior and voluntary alcohol consumption in a selected line of rats that were bred for high alcohol preference.57

Thus, altogether, my hypothesis is that individual differences in stress vulnerability and resilience, which are key determinants of the development of PTSD and addiction, derive from the neurocircuitry of our emotional “dark side.” The origins of activation of the dark side involve both hyperactivity of the extended amygdala (dynorphin and CRF driven by excessive drug use) and reduced activity of the medial PFC (driven by excessive drug use and brain trauma). New advances in our understanding of the neurocircuitry of the dark side and identification of epigenetic factors that weight the function of these circuits will be the key to precision medicine for the diagnosis and treatment of these disorders.

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41.          L.F. Vendruscolo, E. Barbier, J.E. Schlosburg, K.K. Misra, T. Whitfield, Jr., M.L. Logrip, C.L. Rivier, V. Repunte-Canonigo, E.P. Zorrilla, P.P. Sanna, M. Heilig, and G.F. Koob. “Corticosteroid-dependent plasticity mediates compulsive alcohol drinking in rats.” Journal of Neuroscience 32 (2012) 7563-7571.

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- See more at: http://www.dana.org/Cerebrum/2015/The_Darkness_Within__Individual_Differ...

 

Neural Pathways of Stress Integration: Relevance to Alcohol Abuse,James P. Herman, Ph.D.

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James P. Herman, Ph.D.

James P. Herman, Ph.D., is a professor in the Departments of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio.

Stress is a critical component in the development, maintenance, and reinstatement of addictive behaviors, including alcohol use. This article reviews the current state of the literature on the brain’s stress response, focusing on the hypothalamic–pituitary– adrenal (HPA) axis. Stress responses can occur as a reaction to physiological (or systemic) challenge or threat; signals from multiple parts of the brain send input to the paraventricular nucleus (PVN) within the hypothalamus. However, responses also occur to stressors that predict potential threats (psychogenic stressors). Psychogenic responses are mediated by a series of nerve cell connections in the limbic–PVN pathway, with amygdalar and infralimbic cortex circuits signaling excitation and prelimbic cortex and hippocampal neurons signaling stress inhibition. Limbic–PVN connections are relayed by predominantly GABAergic neurons in regions such as the bed nucleus of the stria terminalis and preoptic area. Chronic stress affects the structure and function of limbic stress circuitry and results in enhanced PVN excitability, although the exact mechanism is unknown. Of importance, acute and chronic alcohol exposure are known to affect both systemic and psychogenic stress pathways and may be linked to stress dysregulation by precipitating chronic stress–like changes in amygdalar and prefrontal components of the limbic stress control network.

Key words: Addiction; alcohol and other drug–seeking behavior; alcohol use and abuse; stress; stressor; chronic stress reaction; stress integration; physiological response to stress; psychogenic stress responses; brain; neural pathways; limbic-paraventricular pathway; limbic stress control network; hypothalamic–pituitary– adrenal axis; literature review

Adaptation in the face of physical or psychological adversity is required for the survival, health, and well-being of all organisms. Adverse events, often denoted as “stressors,” initiate a diverse physiological response from multiple sources, including activation of the hypothalamic–pituitary– adrenal (HPA) axis.1 The HPA axis is responsible for the glucocorticoid component of the stress response (i.e., steroid hormone response; cortisol in humans, corticosterone in mice and rats). Glucocorticoid secretion is thought to contribute to stress adaptation by causing long-term changes in gene expression via cognate adrenocorticosteroid receptors (i.e., mineralocorticoid receptor [MR] and glucocorticoid receptor [GR]). The adrenocorticosteroid receptors function as ligand-gated transcription factors (De Kloet et al. 1998) but can also modulate transcription by interfering with other transcriptional regulators, such as nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) (Webster and Cidlowski 1999). Glucocorticoids also can have rapid effects on brain chemistry and behavior via nongenomic membrane signaling mechanisms (De Kloet et al. 2008). Glucocorticoids are thought to contribute to termination of the initial stress response (Keller-Wood and Dallman 1984) and to participate in long-term restoration of homeostasis triggered by the initial response (Munck et al. 1984).


1 For the definition of this and other technical terms, see the Glossary, pp. 522–524.

Glucocorticoid stress responses can be initiated by physiological perturbations (representing reflexive responses) or by brain processes linking environmental cues with probable negative outcomes. The latter so-called “psychogenic” response is anticipatory in nature and involves brain pathways responsible for innate defense programs or memory of aversive events (Herman et al. 2003). Thus, the psychogenic response is related to prior experience, and it is designed to energetically prepare the organism to either avoid an adverse outcome or engage in behaviors that can maximize the potential for survival.

Considerable evidence indicates that stress systems play a major role in addictive processes, including alcohol dependence. For example, exposure to stress can precipitate relapse or increase alcohol use (Sinha 2007). Actions of stress/glucocorticoids on alcohol intake can be linked to modulation of reward/ stress circuitry, including, for example, enhancement of dopamine release in the nucleus accumbens (Sutoo and Akiyama 2002; Yavich and Tiihonen 2000) and activation of central corticotropin-releasing factor (CRF) pathways (Heilig and Koob 2007). Notably, the link between alcohol intake and stress is complicated by the fact that exposure to alcohol, like many drugs of abuse, causes the release of glucocorticoids upon exposure and thus can be classified as an acute “stressor” of sorts (see Allen et al. 2011).

This article reviews the organization of neurocircuits that regulate stress responses, focusing on the HPA axis, which is of particular relevance to addictive processes (see Marinelli and Piazza 2002). It also discusses areas of intersection between stress and reward pathways, as these are likely important in mediating the deleterious effects of stress on substance abuse and addiction.

Circuitry Mediating the Reflexive Stress Response

The HPA axis is controlled by neurons within the paraventricular nucleus (PVN) in the hypothalamus (see figure 1). These neurons secrete CRF and the hormone vasopressin into the portal circulation, which then triggers the release of adrenocorticotropin hormone (ACTH) from the anterior pituitary gland. ACTH travels via the systemic circulation to reach the adrenal cortex, wherein glucocorticoids are synthesized and released (see Herman et al. 2003).

Schematic of hypothalmic-pituitary-adrenal (HPA) axis of the rat

Figure 1 Schematic of the hypothalmic–pituitary–adrenal (HPA) axis of the rat. HPA responses are initiated by neurosecretory neurons of medial parvocellular paraventricular nucleus (mpPVN), which secretes adrenocorticotropin (ACTH) secretagogues such as corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) in the hypophysial portal circulation at the level of the median eminence. These secretagogues promote release of ACTH into the systemic circulation, whereby it promotes synthesis and release of glucocorticoids at the adrenal cortex.

Reflexive stress responses occur during emergencies (e.g., infection, starvation, dehydration, or shock), when the brain must respond to a substantial challenge to homeostasis by mobilizing the HPA axis. Sensory information is communicated to the PVN by first- or second-order neurons, generating a direct activation of CRF release (see Herman et al. 2003). For example, low blood pressure associated with blood loss is relayed via sensory nerves to brainstem neurons in the A2 catecholaminergic cell group (Palkovits and Zaborszky 1977), which then project directly to the PVN (Cunningham and Sawchenko 1988) and rapidly elicit noradrenergic activation of CRF neurons (Plotsky et al. 1989).

In addition to neural pathways, information on changes in physiological state also may be relayed via circulating factors that bind to areas outside the blood–brain barrier. For example, peripheral increases in the hormone angiotensin II (signaling dehydration) are sensed by receptors in the subfornical organ (which is located outside the blood–brain barrier and regulates fluid balance), which sends direct angiotensin II projections to the PVN CRF neurons, facilitating HPA activation (Plotsky et al. 1988). Some peripheral stimuli, such as inflammation, produce factors that can signal by multiple mechanisms; for example, the proinflammatory cytokine interleukin 1-b seems to activate the HPA axis via sensory nerve fibers in the vagus nerve; the area postrema, which is outside the blood–brain barrier; and perivascular cells in the region of the A2 cell group (Ericsson et al. 1997; Lee et al. 1998; Wieczorek and Dunn 2006).

Drugs of abuse also may produce an initial corticosterone response via brainstem PVN-projecting pathways. For example, initial exposure to alcohol causes ACTH and corticosterone release, consistent with alcohol acting as an unconditioned stimulus (Allen et al. 2011). Acute HPA axis activation by alcohol is mediated by brainstem noradrenergic systems (Allen et al. 2011). However, chronic exposure to alcohol significantly blunts HPA axis activation to acute alcohol exposure (Rivier 1995), suggesting that, to some degree, direct HPA excitatory effects of alcohol use habituate over time.

Circuitry Subserving Anticipatory Stress Responses: The Limbic Stress-Control Network

Because true physiologic “emergencies” are relatively rare, the vast majority of stress responses are anticipatory in nature, involving interpretation of the threat potential of environmental stimuli with respect to previous experience or innate programs. Anticipatory stress responses are largely controlled by limbic forebrain structures, such as the hippocampus, medial prefrontal cortex (mPFC), and amygdala (see Ulrich-Lai and Herman 2009). These structures all receive processed sensory information and are involved in regulation of emotion, reward, and mood.

Brain lesion and stimulation studies indicate that the hippocampus inhibits the HPA axis. Electrical stimulation of the hippocampus decreases glucocorticoid release in rats and humans. Damage to the hippocampus, or the nerves carrying impulses away from it (i.e., lateral fornix), cause exaggerated responses to psychogenic stressors (e.g., restraint) and manifest as a prolonged return to baseline glucocorticoid levels (for primary references, see Herman et al. 2003; Jacobson and Sapolsky 1991). Some data suggest that the hippocampus also inhibits basal HPA axis activity, but this is not universally observed (Herman et al. 2003; Jacobson and Sapolsky 1991). The effects of hippocampal damage on psychogenic HPA axis stress responses can be localized to the ventral subiculum (vSUB), the main subcortical output of the ventral hippocampus (Herman et al. 2003). Discrete lesions of the vSUB in rats enhance PVN CRF peptide and mRNA expression and increase corticosterone release and PVN activation (as determined by induction of FOS mRNA expression) in response to restraint (Herman et al. 1998).

The effect of the vSUB on stress regulation is stressor specific. Lesions of the vSUB prolong HPA axis responses to novelty but do not affect reflexive responses (e.g., to ether inhalation) (Herman et al. 1998). Some evidence suggests that glucocorticoids play a role in hippocampal inhibition of anticipatory responses, as lesions can block feedback inhibition of the HPA axis by the synthetic steroid dexamethasone (Magarinos et al. 1987). In addition, mice with forebrain GR deletions, including the hippocampus, have exaggerated responses to restraint and novelty (but not hypoxia) and impaired dexamethasone suppression of corticosterone release (Boyle et al. 2005; Furay et al. 2008). Together, the data indicate that the hippocampus is specifically engaged in regulation of responses to psychogenic stressors, in keeping with its role in cognitive processing and emotion.

Unlike the hippocampus, the amygdala is associated with excitation of the HPA axis. Amygdalar stimulation promotes glucocorticoid release, whereas large lesions of the amygdaloid complex reduce HPA axis activity (see Herman et al. 2003). However, there is a marked subregional specialization of stress-integrative functions within the amygdala. The central nucleus of the amygdala (CeA) is highly responsive to homeostatic stressors, such as inflammation and blood loss (Dayas et al. 2001; Sawchenko et al. 2000). Lesions of the CeA attenuate HPA axis responses to these types of stimuli but not to restraint (Dayas et al. 1999; Prewitt and Herman 1997; Xu et al. 1999). In contrast, the medial nucleus of the amygdala (MeA) shows preferential FOS responses to stimuli, such as restraint (Dayas et al. 2001; Sawchenko et al. 2000). Lesions of the MeA reduce HPA axis responses to restraint and light and sound stimuli but not to systemic injection of the protein interleukin 1-b or ether inhalation (Dayas et al. 1999; Feldman et al. 1994). Thus, it seems that reflexive and anticipatory responses may be regulated in part by discrete amygdaloid circuitry.

The mPFC seems to have a complex role in stress regulation. All divisions of the rodent PFC are robustly activated by acute stress. However, the physiological consequences of stress activation seem to vary by region. The prelimbic division of the mPFC (PL) is important in stress inhibition because numerous studies have shown that damage to this region prolongs HPA axis responses to acute psychogenic (but not homeostatic) stressors (Diorio et al. 1993; Figueiredo et al. 2003; Radley et al. 2006), whereas stimulation inhibits stress responses (Jones et al. 2011). The mPFC seems to be a site for glucocorticoid feedback of HPA responses because local glucocorticoid implants inhibit anticipatory (but not reflexive) responses to stressors (Akana et al. 2001; Diorio et al. 1993). In contrast, lesions directed at the more ventral infralimbic PFC (IL) have a markedly different physiological effect. Damage to the IL decreases autonomic responses to psychogenic stressors (Tavares et al. 2009) and also attenuates PVN Fos activation in response to restraint (Radley et al. 2006). Thus, the PL and IL seem to have opposing effects on stress integration.

Running the Relay: Limbic–PVN Networks

Stimulation of the PVN by the hippocampus, prefrontal cortex, and amygdala is quite limited. Therefore, regulation of HPA axis output by these structures requires intermediary synapses (see figure 2). Studies that trace projections from one part of the brain to another (i.e., tract-tracing studies) reveal the potential for bisynaptic limbic–PVN connections traversing a number of subcortical regions, including the bed nucleus of the stria terminalis (BNST), dorsomedial hypothalamus, medial preoptic area, and peri-PVN region (including the subparaventricular nucleus) (Cullinan et al. 1993; Prewitt and Herman 1998; Vertes 2004). Dual- tracing studies indicate that nerves carrying impulses away from the vSUB, MeA, and CeA (i.e., efferent nerves) directly contact PVN-projecting neurons in these regions, consistent with functional interconnections (Cullinan et al. 1993; Prewitt and Herman 1998).

Schematic of limbic stress-integrative pathways from the prefrontal cortex, amygdala and hippocampus

Figure 2 Schematic of limbic stress-integrative pathways from the prefrontal cortex, amygdala and hippocampus. The medial prefrontal cortex (mPFC) subsumes neurons of the prelimbic (pl) and infralimbic cortices (il), which appear to have different actions on the hypothalmic–pituitary–adrenal (HPA) axis stress response. The pl sends excitatory projections (designated as dark circles, filled line with arrows) to regions such as the peri-PVN (peri-paraventricular nucleus) zone and bed nucleus of the stria terminalis (BNST), both of which send direct GABAergic projections to the medial parvocellular PVN (delineated as open circles, dotted lines ending in squares). This two-neuron chain is likely to be inhibitory in nature. In contrast, the infralimbic cortex projects to regions such as the nucleus of the solitary tract (NTS) and the anterior BNST, which sends excitatory projections to the PVN, implying a means of PVN excitation from this cortical region. The ventral subiculum (vSUB) sends excitatory projections to numerous subcortical regions, including the posterior BNST, peri-PVN region (including the subparaventricular zone [sPVN], medial preoptic area [POA] and ventrolateral region of the dorsomedial hypothalamic nucleus [vlDMH]), all of which send GABAergic projections to the PVN and are likely to communicate transsynaptic inhibition. The medial amygdaloid nucleus (MeA) sends inhibitory projections to GABAergic PVN-projecting populations, such as the BNST, POA and sPVN, eliciting a transsynaptic disinhibition. A similar arrangement likely exists for the central amygdaloid nucleus (CeA), which sends GABAergic outflow to the ventrolateral BST and to a lesser extent, the vlDMH. The CeA also projects to GABAergic neurons
in the NTS, which may disinhibit ascending projections to the PVN.

The differential effects of PL and IL on stress effector systems may reflect their marked divergence in subcortical targets. The PL has substantial projections to reward-relevant pathways, including the nucleus accumbens and basolateral amygdala, as well as the posterior BNST, which is linked to HPA axis inhibition. In contrast, the IL has rich interconnections with regions involved in autonomic regulation, including the CeA, nucleus of the solitary tract (NTS), anteroventral BNST, and dorsomedial hypothalamus (Vertes 2004). Thus, it is probable that the net effect of PFC stress activation requires subcortical integration of PL and IL outflow.

Of note, mPFC, hippocampal, and amygdalar efferents tend to be concentrated in regions sending γ-aminobutyric acid (GABA)-carrying projections to the PVN (see figure 2). Indeed, the vast number of sub-innervated PVN-projecting neurons are GABAergic in phenotype. Projection neurons of the vSUB (as well as the mPFC) are glutamatergic in nature, thus suggesting that these cells engage in transsynaptic inhibition of the PVN following activation by stress. In contrast, the projection neurons of the MeA and CeA are predominantly GABAergic, suggesting that amygdalar excitation of the PVN is mediated by disinhibition, involving sequential GABA synapses (Herman et al. 2003).

The BNST is of particular interest, in that it receives inputs from all of the major limbic stress-integrative structures (CeA, MeA, vSUB, IL, and PL) (Cullinan et al. 1993; Dong et al. 2001; Vertes 2004). Of note, different BNST subregions seem to be responsible for inhibition versus excitation of HPA axis stress responses. For example, lesions of the posterior medial region of the BNST increase the magnitude of ACTH and corticosterone release and PVN Fos activation (Choi et al. 2007), implying a role in central integration of stress inhibition. Lesions of the anteroventral component of the BNST also enhance stress responses (Radley et al. 2009). In contrast, larger lesions of the anterior BNST reduce HPA axis stress responses (Choi et al. 2007), consistent with a role for this region in stress excitation. Thus, the role of the BNST in stress inhibition versus activation is compartmentalized and may be associated with differences in limbic targeting of individual subregions of the BNST. For example, the posterior medial BNST receives heavy innervation from the vSUB and MeA, whereas the anteroventral region receives input from the CeA and most of the IL efferents (Canteras and Swanson 1992; Cullinan et al. 1993; Dong et al. 2001; Vertes 2004).

The medial preoptic area and peri-PVN regions are heavily populated with GABAergic neurons and seem

to primarily modulate stress inhibition (Herman et al. 2003). Neurons in these regions are believed to provide tonic inhibition to the PVN, which can be adjusted in accordance with glutamate inputs from the vSUB (enhanced inhibition) or GABAergic inputs primarily from the MeA (disinhibition). Lesions of the medial preoptic nucleus increase HPA axis stress responses and block HPA axis responses elicited by medial amygdalar stimulation, suggesting a primary role in stress inhibition (for primary references, see Herman et al. 2003). Local inhibition of glutamate signaling in the peri-PVN region also enhances HPA axis stress responses (Ziegler and Herman 2000), suggesting that limbic axons terminating in this region may modulate PVN activation.

It is more difficult to pinpoint the role of other hypothalamic regions linking limbic efferents to the PVN, such as the dorsomedial nucleus (Herman et al. 2003). For example, conflicting results are observed following lesion, activation, or inactivation of this dorsomedial hypothalamus, possibly because of heavy mixing of glutamate and GABA neuronal populations (Herman et al. 2003).

Additional potential relays remain to be fully explored. For example, the raphe nuclei and NTS innervate the PVN, are targeted by limbic structures (such as the PL) (see Vertes 2004) and are involved in stress excitation by serotonin and norepinephrine (Herman et al. 2003), respectively. However, as yet, there are no anatomical studies describing bisynaptic limbic–PVN relays through these regions.

Circuitry Subserving Chronic Stress Responses

Prolonged or extended exposure to stress causes long-term upregulation of the HPA axis, characterized by reduced thymus weight (attributed to cumulative elevations in GCs); increased adrenal size (attributed to increased ACTH release); increased adrenal sensitivity to ACTH; facilitated HPA axis responses to novel stressors; and in some (but

not all) paradigms/conditions, elevated basal GC secretion (see Herman et al. 1995; Ulrich-Lai et al. 2006). Changes in peripheral hormone release are accompanied by increased PVN CRF and vasopressin mRNA (Herman et al. 1995), suggesting that HPA upregulation is centrally mediated. In addition, chronic stress increases glutamatergic and noradrenergic terminal abutting PVN CRF neuronal somata and dendrites, consistent with enhanced excitatory synaptic drive (Flak et al. 2009).

Central mechanisms of chronic HPA axis activation have yet to be determined. The role of the limbic forebrain in stress control suggests that differential involvement of the PFC, hippocampus, and amygdala may be responsible for prolonged drive. Of note, all regions show significant chronic stress–induced neuroplastic changes: Dendritic retraction is evident in hippocampal and mPFC pyramidal neurons, whereas dendritic extension is observed in the amygdala (for primary references, see Ulrich-Lai and Herman 2009). These studies are consistent with redistribution of limbic input to HPA excitatory circuits, favoring excitation over inhibition.

Enhanced amygdalar drive is proposed to play a major role in chronic stress pathology. For example, chronic stress activates the CeA CRF system, which has been proposed as a chronic stress–recruited pathway (Dallman et al. 2003). However, the CeA does not seem to be required for the development or maintenance of chronic stress symptoms (Solomon et al. 2010). In addition, lesions of the MeA also fail to prevent chronic stress drive of the HPA axis (Solomon et al. 2010). Thus, the overall link between amygdalar hyperactivity and chronic stress–induced HPA axis dysfunction has yet to be firmly established.

The paraventricular nucleus of the hypothalamus (PVT) seems to comprise a component of the chronic-stress pathway. Lesions of the PVT block chronic stress sensitization of HPA axis responses to novel stressors (Bhatnagar and Dallman 1998), suggesting a primary role in the facilitation process.

In addition, PVT lesions disrupt the process of HPA axis habituation to repeated stressors (Bhatnagar et al. 2002). Taken together, the data suggest the PVT plays a major role in gating HPA axis drive in the context of prolonged stress exposure. Of note, the PVT and limbic forebrain sites that control acute stress responses are interconnected (see Vertes and Hoover 2008), allowing for possible coordination of corticolimbic stress outputs in this region. The PVT also is positioned to process information regarding ongoing physiological status, receiving inputs from orexinergic neurons (which regulate the release of acetylcholine, serotonin, and noradrenaline) of the dorsolateral hypothalamus (which plays an integral role in control of arousal processes) and ascending brainstem systems involved in autonomic control.

The BNST also is positioned to integrate information on chronic stress. Lesions of the anteroventral BNST attenuate responses to acute stress, but potentiate facilitation of the HPA axis by chronic stress (Choi et al. 2008). These data suggest that this region has chronicity-dependent roles in HPA axis control, with presumably different neural populations recruited in an attempt to respond to prolonged stress exposure. Given intimate interconnectivity between the anterior BNST and mPFC, hippocampus, and amygdala, it is possible that BNST neurons may be “reprogrammed” by chronic stress– induced changes in limbic activity or innervation patterns.

Stress Circuitry and Alcohol

Readers familiar with the alcohol literature will no doubt find considerable overlap between the stress circuitry described above and brain circuitry linked to alcohol intake. For example, considerable data support a role for the CeA, BNST, and noradrenergic systems in the maintenance of alcohol dependence (see Koob 2009), suggesting that the process of addiction is linked to activation of stress (and HPA axis) excitatory pathways. Indeed, enhanced CeA/BNST CRF expression resembles what would be expected after chronic stress, leading to the hypothesis that negative addictive states (e.g., avoidance of withdrawal) are linked to alcohol-induced recruitment of chronic stress circuits (Koob 2009). Conversely, activation of reward pathways is known to significantly buffer stress reactivity via the amygdaloid complex, suggesting a mechanism whereby the rewarding effects of alcohol may reduce perceived stress (Ulrich-Lai et al. 2010).

Alcohol also has profound effects on medial prefrontal cortical neural activity, and chronic use is associated with prefrontal hypofunction (poor impulse control) in humans (see Abernathy et al. 2010). The mPFC projects to both the CeA and BNST and, at least in the case of the prelimbic region, plays a prominent role in HPA inhibition. In combination with the gain of function seen in amygdalar–BNST circuits, these observations suggest that chronic alcohol use causes marked changes across the limbic stress control network, biasing the organism for stress hyperreactivity.

Overall, adequate control of the HPA axis is a requirement for both short- and long-term survival. Given that key control nodes of HPA axis activity are targeted by alcohol, and that alcohol itself constitutes a threat, it is not surprising that corticosteroids, the “business end” of the axis, have profound interactions with both behavioral and physiological regulation of intake. The overlap between HPA regulatory and addiction circuits identifies key points that may be targets for both the long-term detrimental effects of alcohol abuse as well as dependence itself. The importance of circuit overlap is further underscored by the powerful reciprocal relationship between life stress and drinking, which complicates efforts to establish and maintain abstinence.

Acknowledgements

This work was supported by grants MH–049698, MH–069680, and MH–069725.

Financial Disclosure

The author declares that he has no competing financial interests.

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A Role for Brain Stress Systems in Addiction (2008)

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

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Abstract

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

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

1.2. Dynamics of Addiction

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

Table 1 
Definitions
Table 2 
Stages of the Addiction Cycle

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

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

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

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

1.3. Motivation, Opponent Process, and Stress

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

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

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

1.4 Hypothalamic-Pituitary-Adrenal Axis

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

1.5. Extended Amygdala: Interface of Stress and Addiction

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

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

2.1. Corticotropin-Releasing Factor

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

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

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

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

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

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

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

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

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

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

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

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

2.2. Norepinephrine

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

Figure 4 
Localizations and Projections of Brain Stress Systems—Norepinephrine

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

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

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

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

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

2.3. Dynorphin/κ Opioid System

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

Figure 5 
Localizations and Projections of Brain Stress Systems—Dynorphin

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

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

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

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

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

2.4. Orexin

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

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

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

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

2.5. Vasopressin

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

Figure 7 
Localizations and Projections of Brain Stress Systems—Vasopressin

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

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

3.1. Neuropeptide Y

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

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

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

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

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

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

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

3.2. Nociceptin (Orphanin FQ)

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

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

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

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

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

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

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

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

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

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

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

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

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

5. Neurocircuitry of the Brain Stress Systems in Dependence

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

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

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

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

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

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

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

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

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

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

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

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

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

6.1. Hypothalamic-Pituitary-Adrenal Axis as a Facilitator

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

6.2. Opponent Process/Between-System Neuroadaptations

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

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

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

6.3. Stress Systems in Relapse

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

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

6.4. Allostasis and Addiction

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

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

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

Acknowledgments

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

Footnotes

SUPPLEMENTAL DATA

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

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Acute Stress Influences Neural Circuits of Reward Processing (2012)

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

This article has been cited by other articles in PMC.

Abstract

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

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

Introduction

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

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

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

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

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

Materials and Methods

Participants

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

Procedure

Stress induction

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

Card guessing task

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

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

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

Salivary cortisol measurements

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

fMRI acquisition and analysis

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

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

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

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

Results

Reaction time data

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

Subjective stress ratings

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

Salivary cortisol data

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

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

fMRI results

Outcome valence: reward – punishment by experimental group contrast

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

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

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

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

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

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

Outcome magnitude: high – low by experimental group contrasts

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

Exploratory analyses: sex effects

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

Discussion

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

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

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

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

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

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

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

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

Conflict of Interest Statement

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

Acknowledgments

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

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Addiction and the adrenal cortex (2013)

Published online before print 2013, doi: 10.1530/EC-13-0028 Endocr Connect vol. 2 no. 3 R1-R14 

  1. Caroline H Brennan

+ Author Affiliations

  1. School of Biological and Chemical Sciences, Queen Mary University of London, London E1 4NS, UK
  2. Correspondence should be addressed to G P Vinson Email: g.p.vinson@qmul.ac.uk

Abstract

Substantial evidence shows that the hypophyseal–pituitary–adrenal (HPA) axis and corticosteroids are involved in the process of addiction to a variety of agents, and the adrenal cortex has a key role. In general, plasma concentrations of cortisol (or corticosterone in rats or mice) increase on drug withdrawal in a manner that suggests correlation with the behavioural and symptomatic sequelae both in man and in experimental animals. Corticosteroid levels fall back to normal values in resumption of drug intake. The possible interactions between brain corticotrophin releasing hormone (CRH) and proopiomelanocortin (POMC) products and the systemic HPA, and additionally with the local CRH–POMC system in the adrenal gland itself, are complex. Nevertheless, the evidence increasingly suggests that all may be interlinked and that CRH in the brain and brain POMC products interact with the blood-borne HPA directly or indirectly. Corticosteroids themselves are known to affect mood profoundly and may themselves be addictive. Additionally, there is a heightened susceptibility for addicted subjects to relapse in conditions that are associated with change in HPA activity, such as in stress, or at different times of the day. Recent studies give compelling evidence that a significant part of the array of addictive symptoms is directly attributable to the secretory activity of the adrenal cortex and the actions of corticosteroids. Additionally, sex differences in addiction may also be attributable to adrenocortical function: in humans, males may be protected through higher secretion of DHEA (and DHEAS), and in rats, females may be more susceptible because of higher corticosterone secretion.

Keywords

Introduction

The purpose of this review is to demonstrate the critical role of the adrenal cortex in addiction and additionally to propose that sex differences in adrenocortical function may contribute to sex differences in addiction. Where it is clear, the sex of experimental animals or of human subjects in the cited studies is stated, although in most cases sex differences were not emphasized.

There is a long history of associating addiction with the adrenal. Indeed, it was well before the adrenocortical hormones were even characterized that morphine toxicity was linked to the adrenal gland. Thus, Lewis (1) and Mackay & Mackay (2) showed that adrenalectomy increased morphine sensitivity in female rats, and chronic treatment with morphine in males or methadone in either sex produces adrenocortical hypertrophy (3, 4). Consequently, there has been interest in the actions of the hormones of the adrenal as possible agents in addiction from the time of their discovery. Treatment with cortisone (the therapeutic corticosteroid of choice at the time) was soon applied in the management of meperidine and morphine withdrawal symptoms in men (5), apparently with beneficial effects, while Lovell associated alcoholism and drug addiction with hypoadrenocorticism (6).

More systematic study then discounted corticosteroids along with other novel ‘cures’ for withdrawal symptoms, and Fraser & Isbell (7) were the first to suggest that in fact withdrawal symptoms (from morphine) in men were associated with eosinopaenia, a measure used at that time to reflect high levels of circulating corticosteroids (8). Eosinophil counts swiftly normalized when morphine was restored. These authors also found that treatment with either cortisone or ACTH shortened the period for development of withdrawal symptoms in men, and therefore, they themselves could be considered a cause (7, 9, 10, 11). Indeed, chronic treatment with corticosteroid can itself lead to later withdrawal symptoms (12).

So there are fundamental questions on the role of corticosteroids in addiction. Is the lower adrenocortical activity in sustained morphine administration, and its elevation when administration ceases, a cause or an effect of addictive responses? Could the drive to addictive drugs actually represent a drive to lower cortisol, with its sequelae? Or is the heightened secretion of corticosteroids in drug withdrawal simply a response to stress? We here argue that the adrenal cortex has a critical role in the acquisition of addiction and also in protection against it.

The hypophyseal–pituitary–adrenal axis in the brain and addiction

In relation to addiction, far more attention has been paid to hypophyseal–pituitary–adrenal (HPA) components in the brain than to the systemic (i.e. blood-borne) HPA axis. All the components are present in the brain, and, in relation to the hypothesis that the adrenal itself is crucial to addiction, it is important to unravel the relationship between brain and systemic HPA function. This section examines the evidence for brain HPA function in addiction and shows that it is not autonomous, and its function is closely regulated by and linked to the systemic HPA.

Corticotrophin releasing hormone

Corticotrophin releasing hormone (CRH) is produced in various parts of the brain (13). First, CRH exerts its systemic effects following its release at the median eminence by neuronal tracts that originate in the paraventricular nucleus (PVN) of the hypothalamus. CRH is transported to the corticotrophs of the anterior pituitary via the hypophyseal portal system and then stimulates the secretion of ACTH. ACTH is in turn carried in the general circulation and stimulates the secretion of corticosteroids in the adrenal cortex.

In addition, however, CRH, its receptors CRHR1 and CRHR2, and also CRH binding protein (CRH-BP), which modulates CRH actions, are found in other brain locations, where CRH presumably acts primarily as a neurotransmitter. These sites include the cerebrocortex, limbic system, hippocampus, amygdala, locus coeruleus, olfactory bulb and cerebellum (14, 15, 16, 17, 18, 19, 20). While the involvement of such extra hypophyseal CRH with addiction may be independent of the HPA (18, 20), there are certainly pathways through which it contributes to the multifactorial regulation of hypothalamic CRH (Fig. 1).

Figure 1 
View larger version: 
Figure 1 

The expanded HPA axis. From (20, 49, 80, 82, 192, 193) and see text. BNST, bed nucleus of stria terminalis; PFC, pre-frontal cortex; PVN, paraventricular nucleus; VTA, ventral tegumental area (associated with reward responses); CRH, corticotrophin releasing hormone; POMC, proopiomelanocortin; +, stimulatory; −, inhibitory. Solid arrows show proven regulation, and dotted arrows show postulated actions. Secreted CRH is indicated in blue lettering, and sites of CRH and POMC signalling are indicated in red and green respectively: here, arrows indicate regulatory pathways that are unquestionably multifactorial but may include actions of CRH and POMC peptides. The inhibitory effect of neural POMC peptides on PVN CRH is particularly interesting, and, by comparison with other systems, might suggest a negative feedback mechanism; however, there is little evidence for reciprocal feedback of CRH on POMC in the brain. Instead, regulation of neural POMC is multifactorial (e.g. (65, 67), and this is primarily linked to its role in energy balance and nutrition, see text. There is, however, much evidence to show the feedback of glucocorticoids on CRH expression in several brain regions. Mostly, this is negative, except in the amygdala, a key region in addiction (19), where it is positive.

 

In the brain, CRH binds to both receptor types, CRHR1 and CRHR2. In addition to CRH itself, both these receptors bind ligands of the urotensin family. The two receptors mediate different responses; CRHR1 agonists produce stress-related responses on which CRHR2 may have less effect, while more potently depressing food intake (21, 22, 23, 24).

There is certainly substantial evidence for the role of CRH in addiction (18, 25), and particularly in reinstatement, but the data are not always consistent. For example, cocaine stimulates the HPA axis through a hypothalamic/CRH-mediated mechanism in male rats (26, 27), and although this is not invariably closely linked to corticosterone (28), both Crh mRNA transcription and circulating corticosterone are further increased on cocaine withdrawal (29). In contrast, shock-induced reinstatement of heroin or alcohol seeking clearly depends on CRH, but not on corticosterone, according to some authors (30, 31, 32). Nevertheless, adrenal function is required during cocaine self-administration for subsequent CRH-dependent shock-induced reinstatement to occur (33). The modulator of CRH actions, CRH-BP, is now emerging as an additional factor, although not so widely studied in the addiction field (34, 35). Although both corticosterone and ACTH secretion are increased by acute alcohol exposure, they are inhibited in chronic exposure (36, 37). Neither CRH nor cortisol is implicated in cocaine reinstatement in squirrel monkeys (38).

With specific regard to morphine and the opioids, it is clear that reduced circulating corticosteroid concentrations may be a consequence of opioid inhibition of CRH secretion, acting through μ- and κ-type opioid receptors in the male rat hypothalamus (39, 40, 41). In humans, opioids directly inhibit CRH secretion and the HPA axis, resulting in decreased circulating cortisol. In male rats, the effect is biphasic, with early enhancement of CRH (and the HPA) followed by inhibition after a few days of treatment (41, 42); such responses are affected by stress in male rats (43). Indeed, the evidence suggests that opioidergic mechanisms may at least partially underlie both the behavioural effects of CRH in male rats (44) and also the increase in CRH secretion under conditions of stress. This may not be true in other situations such as the increased HPA activity in adrenalectomized animals (45). This double effect in rats may be because opioids have differential effects on different cell types: they certainly inhibit CRH secretion that is promoted by neurotransmitters (46). The possibly critical involvement of opioids in alcohol addiction in humans (47) has also been shown to be exerted via other than HPA pathways (48).

There are clear differences between the actions of different addictive drugs on Crh mRNA transcription in the hypothalamus, and although alcohol acts directly on the PVN, other drugs, including cocaine, nicotine and cannabinoids, activate Crh transcription in other brain sites (49). Adrenocortical activity may still be critical, for example in reinstatement of cocaine addiction in male rats (33). Timing of exposure is also significant; early exposure can affect subsequent responses (50), and in male rats, adolescent exposure to alcohol vapour blunts subsequent adult Crh transcription response to acute alcohol (51).

The development of specific CRHR1 antagonists has provided more information. CRHR1 blockade inhibits further alcohol drinking in male rats habituated to a high intake (52), and, in conjunction with additional studies using Crh1 knockout animals, it has been shown that CRHR1 signalling pathways are essential for sensitization to alcohol addiction in male mice (53); a common expression of neuroadaptations induced by repeated exposure to addictive drugs is a persistent sensitized behavioural response to their stimulant properties. These authors also show that acquisition and sensitization are differentially regulated. Acquisition involves the HPA axis and is inhibited by the glucocorticoid blocker mifepristone as well as by CRHR1 blockade, whereas sensitization is unaffected by mifepristone. Pastor et al. (53) propose that this suggests a non-hypothalamic CRHR1-linked pathway in sensitization. Different effects were seen in methamphetamine (MA) responses, in which behavioural sensitization measured as increased drug-induced locomotor activity was unaffected in Crh1 knockouts or by the antagonist CP 154 526 in DBA/2J mice, whereas deletion of Crh2 attenuated MA-induced behavioural sensitization. Here, an action of endogenous urocortins was suggested, focused in the basolateral and central nuclei of the amygdala (54).

Proopiomelanocortin

Proopiomelanocortin (POMC) provides, in ACTH and α-melanocyte stimulating hormone (α-MSH), the other components of the HPA axis, and in this context, its primary site of expression and processing is the anterior pituitary and (in rodents) the pars intermedia. POMC is also expressed in brain sites, primarily in projections from the arcuate nucleus of the hypothalamus and from the nucleus tractus solitarius of the brainstem (55, 56, 57). Its primary role in the brain is the generation of α-MSH, which participates in the regulation of food intake and in the production of β-endorphin, pain control. α-MSH acts through two of the melanocortin receptor (MCR) series, MC3R and MC4R, and the latter may also regulate aspects of pain recognition (25, 58).

POMC expression and processing suggests that although ACTH and other POMC products such as β-endorphin can be found in non-hypothalamic regions of the brain or cerebrospinal fluid (59, 60), some may be transported to the brain from the blood (60, 61). From early development, the major adrenocortical-related POMC product in the brain is α-MSH (62), presumably associated with the distribution of the prohormone convertases PC1 and PC2 (63, 64). By far, the major focus of attention in this regard is the role of α-MSH with leptin, ghrelin and agouti protein in the regulation of food intake and energy balance (56, 62, 65, 66, 67, 68).

In addition to its role in energy balance, α-MSH also plays a part in the physiology of addiction, and MC4R, like CRH receptors, respond to morphine (69, 70, 71), and the behavioural effects of morphine or cocaine are modulated by selective MC4R inhibition (72, 73). Additionally, acute alcohol treatment reduced α-MSH expression in hypothalamic and other brain locations in rats, but chronic treatment enhanced it (74).

Of course, POMC processing in relation to addiction cannot be considered purely in terms of its HPA-linked functions. The production of β-endorphin leads inevitably to direct effects on addiction pathways. Its main action is mediated by μ-receptors as are the opiates morphine, heroin and methadone, and in humans, the endogenous opiates are similarly inhibitory on HPA function, although both stimulatory and inhibitory in rats (49, 75).

What has not been clear hitherto is whether the term ‘HPA axis’ can in reality be extended to these components in the brain. In other words, it has been unclear whether, for example, non-hypothalamic CRH provokes synthesis, processing or release of POMC in the brain, but the different locations of the expression of these components may suggest it does not (Fig. 1). Similarly, there has really been no evidence that brain CRH or POMC products have any interaction with the adrenal cortex and the secretion of glucocorticoids, other than via the hypothalamus. On the contrary, it has sometimes been assumed that they do not (e.g. (53)). However, neural glucocorticoid receptor (GR) disruption, including in the PVN, ameliorates the effects of anxiety and also results in heightened HPA activity in male mice (76), consistent with the loss of glucocorticoid inhibition of CRH (20, 77). In contrast, forebrain-specific GR knockout, which does not involve the PVN, increased anxiety behaviour but has the same effect of diminishing glucocorticoid inhibition of CRH in male mice (77). It is clear from this study that the HPA is regulated partly by forebrain GR-mediated inhibition. Accordingly, what needs to be unravelled is the significance of the local brain CRH/POMC components in distinction to that of the systemic HPA, and how independent these systems really are in addiction.

Interaction between brain CRH and α-MSH

Although the main recognized function of α-MSH in the brain, regulation of food intake and nutrition seems not to be closely related to that of CRH, in fact there is ample evidence of crosstalk between them. Certainly, like the systemic HPA, POMC-processing neurones are activated by stress and play a role in the consequent behavioural response in male rats (78, 79). Furthermore, neuronal POMC-derived peptides regulate hypothalamic CRH and thus ACTH secretion in male and female mice (80). Additionally, α-MSH stimulates Crh transcription in the PVN of male rats (81, 82), although, like γ-MSH, it also inhibits interleukin-1β-induced HPA activity, apparently through central MCRs (83). That the circuit connecting brain and systemic HPA is complete is suggested by the finding that glucocorticoids enhance MC4R signalling in a hypothalamic neuronal cell line (84). We can therefore predict the existence of an extended HPA axis in which the same components, CRH, POMC products and corticosteroids as in the classical system, also interact in the brain (Fig. 1) with specific effects on mood and behaviour. The two systems, brain and somatic, interact to the extent that whatever physiological stimuli activate the systemic system, broadly ‘stress’ and the clock, must also have consequences on mood and behaviour.

Steroids in the brain

The spectrum of structures and functions of neurosteroids is so wide as to form a branch of endocrinology (or at least paracrinology) in its own right. Many are locally synthesized, although usually requiring substrates from non-neural sources. Oestrogens are prominent among these and are produced by aromatase activity in the hippocampus, acting, it is thought, on locally produced C19 steroid substrates (85). They have roles in neural plasticity (86) and neuroprotection (85, 87, 88) and regulate the function of other neurally active agents, including neuroprogesterone, which is also synthesized locally (89). There are sex-related differences in the neural responses to oestrogen (90, 91, 92). Oestrogen action in the brain is mediated through classical oestrogen receptors α and β and also through membrane metabotropic glutamate receptors (93, 94). Neuroactive steroids that primarily act through N-methyl-d-aspartate or gamma-aminobutyric acid (GABA) receptors include the adrenal androgen DHEA, which as DHEAS conjugate is the most abundant steroid in human plasma (95, 96, 97, 98). DHEA is not secreted by the rat adrenal cortex: its presence and activity in the brain reflect its local synthesis (99). DHEA and pregnenolone, both Δ5,3β-hydrosteroids, are also opioid sigma receptor agonists, whereas progesterone, which has the Δ4,3-one configuration, is an antagonist (100). Through their sigma-1 agonist actions, pretreatment with DHEA or pregnenolone potentiates cocaine-induced conditioned place preference (CPP) behaviour in mice (100) but attenuates cocaine-seeking behaviour (101). In patients, DHEA and DHEAS are associated with beneficial actions in cocaine withdrawal (102, 103), and the use of DHEA administration to assist opioid withdrawal has been studied, with variable outcomes (104, 105).

Other known neurosteroids include 3α-hydroxy-5α-pregnan-20-one (tertrahydroprogesterone, allopregnanolone, THP) and 3α,21-dihydroxy-5α-pregnan-20-one (tetrahydrodeoxycorticosterone, THDOC), and they are formed in the brain from progesterone and deoxycorticosterone (106, 107). They have anxiolytic, anti-convulsant and sedative activities and are known to be elevated in both plasma and brain in response to ethanol in rats (106, 108). In addition, the HPA axis is under tonic GABA inhibition at the hypothalamic level (75). Importantly, production in the brain of both THP and THDOC depends on precursor steroids of adrenal origin (106).

The corticosteroids themselves have neurological effects, and brain concentrations of corticosterone certainly have relevance to addictive behaviour in male rats (109), and see below. However, the relevance of local brain synthesis of corticosteroids is unclear. Certainly, all the required enzymes of the corticosteroid biosynthetic pathway from cholesterol are present, notably in the hippocampus, together with the StAR protein (110, 111, 112), but their level of production is likely to be low in comparison with concentrations crossing the blood–brain barrier, and they are not thought to be produced in the brain to any great extent (113, 114). Remarkably then, of the known neurosteroids, the corticosteroids may fall into a group of their own being predominantly dependent on an extraneural source: the adrenal cortex.

The role of the adrenal cortex

Corticosteroids and mood

Clearly, the role of corticosteroids in addiction cannot be understood without reference to the nature of the psychological and behavioural aspects of the actions of corticosteroids themselves. Almost as the corticosteroids were first characterized, their paradoxical capacity to generate both euphoria and depression in humans has been well known, although poorly understood (115, 116). Changes in mood are a feature of chronic corticosteroid therapy, with mild euphoria in the short term and increases in severity of symptoms associated with depression, or even psychosis in the long-term, and these occur most frequently in women (116, 117, 118, 119, 120), although with large variations in incidence in different studies. Moreover, both cortisol levels and the response to ACTH are higher in depression or depressive episodes (121), and animal experiments show that both of these may be linked to high CRH secretion (29). It has been suggested that corticosteroids may have a role in dopamine-related psychiatric disorders (122), and it has also been speculated that some behavioural features in animals and humans may result from structural or other changes in the brain that corticosteroids may invoke, or at least facilitate (114, 123, 124). Reduction of circulating corticosteroid levels, in combination with other indices, can also be used as a marker for response to anxiolytic therapy (125, 126). It has been postulated that depression in fact reflects GR desensitization, giving rise to impaired glucocorticoid feedback at the hypothalamus, hence increased HPA activity. In this model, one action of antidepressants is thus to resensitize GR transcriptional activity (125), independent of their action on monoamine reuptake, but perhaps involving regulation of steroid elimination from the cell through the multi-drug resistance P-glycoprotein membrane transporter system (127, 128). Together, these studies suggest that corticosteroid-evoked mood changes could be related to behavioural responses to addiction.

Corticosteroids and addiction

Although the earlier association between the adrenal cortex and addiction is derived largely from circumstantial evidence, there are now data showing a direct causal link. From their experiences with patients receiving chronic steroid treatment, some authors have been willing to label the corticosteroids as drugs of addiction themselves (129, 130, 131, 132, 133, 134), although much of the earlier evidence is based on individual case reports. These findings tend to suggest a close link between corticosteroids and addiction, a concept amply borne out by more recent studies. Alcohol administration induces ACTH secretion and thus adrenocortical stimulation in male rats (106). In habituated men smoking high- but not low-nicotine cigarettes, increased plasma ACTH and cortisol occurs within minutes of smoking (135). Further evidence for the crucial actions of elevated cortisol is given by its association with impaired learning and memory in abstinent cocaine-dependent men and women (136), although higher basal cortisol levels are associated with improved memory performance in healthy controls. These effects on memory apparently reflect the inverted U-shaped cortisol response curve; at low levels, increased cortisol is beneficial to hippocampal cognitive responses, but at higher levels, it is not (137). The degree of stress-induced cortisolaemia and mood negativity is correlated with increased positivity after amphetamine in men and women (138).

Furthermore, much experimental evidence supports the general concept (see Table 1). Male rats too self-administer corticosterone in a manner that suggests some degree of dependence (139, 140). Thus, de Jong et al. (141) found that cocaine-induced locomotor sensitization in adrenalectomized male mice was restored by replacement of both adrenaline and corticosterone, and cocaine- or alcohol-induced behaviours in female mice are inhibited in the presence of a GR inhibitor (142). Additionally, if corticosteroid synthesis is blocked, cocaine self-administration also relapses according to some authors (143). Others find the reverse that corticosterone facilitates relapse, although dexamethasone did not, suggesting mineralocorticoid receptor (NR3C2, MR) involvement (144). Such effects, like those of antipsychotic drugs, may be mediated through the mesolimbic dopaminergic system (145, 146). It is striking that dopamine-dependent responses to morphine require glucocorticoid receptors (147).

In experimental animals, the definitive evidence for the pivotal role of the corticosteroids in addiction stems from recent studies in the effects of GR over- and under-expression. Brain-specific GR depletion in mice decreased cocaine self-administration, while corticosterone replacement restored it (148). Specific GR disruption in dopaminoceptive but not dopamine neurones decreased cocaine self-administration (149), whereas GR disruption in either type attenuates cocaine-induced CPP, with no effect on morphine-induced behaviour (150). Morphine-induced CPP depends on hippocampal and nucleus accumbens GR (151). In male mice, overexpression of forebrain GR results in heightened sensitization to cocaine as well as anxiety (152).

There is also evidence of the pivotal role of GR in studies of GR polymorphisms in humans, which have revealed association of particular alleles with the initiation of alcohol abuse in female adolescents (153). These and further experimental data that now link addictive behaviour and symptoms with corticosteroids, particularly in response to cocaine, are summarized in Table 1.

View this table: 
Table 1 

Glucocorticoids and addiction. All the direct experimental evidence for the essential role of glucocorticoids has been obtained in experimental animals, as illustrated here. Evidence from the human species is indirect and circumstantial but appears to support the general conclusion that glucocorticoids, regulated by an expanded HPA axis, underlie the important features of addiction.

 

Sex differences in addiction

The possibility of sex differences in responses to drugs of addiction of brain CRH, POMC, neurosteroids and the HPA axis has not been addressed anywhere in the literature reviewed here. Sometimes, the sex of experimental animals used is not actually given, although this is rare. The impression is that studies are often performed on animals of the same sex – male rats are frequently used – to minimize variance. Yet sex differences in addiction are clear and the extensive evidence has been reviewed in human subjects and in experimental animals. Thus, women are more susceptible to addiction and are at greater risk of relapse than men (154, 155), and female rats are more susceptible than male rats. Substantial evidence links this to gonadal hormones (156).

There is nevertheless good reason to speculate that adrenocortical hormones are involved here as well. Both humans and rats have sex differences in adrenocortical function, and although different in nature, both may contribute to sex differences in addiction.

In humans, differences in circulating cortisol in males and females are marginal at most, though there may be differences in responsiveness to ACTH (96, 157, 158). However, the major product of the gland is in fact DHEA, which is secreted not only as the free steroid, but also, and predominantly, as the sulphate, DHEAS. Plasma concentrations of DHEA and DHEAS in young adult men are about 12 nM and 10 μM respectively, compared with about 8 nM and <7 μM in women, levels decrease with age but the sex differences are maintained (96, 159, 160, 161).

The point is that DHEA has been shown to be protective against drugs of addiction, as previously noted. Evidence from cerebrospinal fluid suggests that adrenal DHEA, and even DHEAS, may reach the brain in significant amounts (162), although how this relates to amounts synthesized within the brain cannot be assessed. Although no sex differences in cerebrospinal fluid were reported, it remains plausible that men receive more DHEA protection to addictive drugs than women (154, 162).

In rats, the situation is different, and there is no significant adrenal secretion of DHEA. However, there is a profound difference in secretion and circulating concentrations of corticosterone (the main glucocorticoid in the rat); adult female adrenals are nearly twice the size of males; and output of corticosterone is proportionately greater (163, 164, 165, 166). Although as noted earlier, DHEA is synthesized in the rat brain, there is no sex difference, and brain concentrations are similar in males and females (167). Accordingly, in the rat, it is plausible that heightened sensitivity to addictive drugs in females is associated with the higher circulating levels of corticosterone.

The adrenal, addiction and the clock

If it is the adrenal gland itself that is critical for HPA-modulated addictive processes, then other factors that are instrumental in generating adrenocortical responses may be expected to interact with addiction. Of the physiological stimuli that stimulate the adrenal cortex, stress is the most prominent and relevant. However, an equally potent regulator of the adrenal cortex is the clock.

That stress, however defined, facilitates addiction in both patients and animal models is well understood (168, 169, 170, 171, 172). It is deeply interesting to note that clock time too has its effect on addictive craving and behaviours, although this literature generally has little reference to the HPA, but has been focused on the pineal and melatonin in the brain of male mice (173), or, primarily, on clock genes. Periodicity in PER1 and cocaine sensitivity are associated in male rats and mice of various strains (174), drug reinstatement can be suppressed by photoperiod in male rats (175), and clock gene variants are associated with cocaine sensitization in Drosophila (176) as with addiction in mice (sex not given) (177) and in humans, according to some authors (178, 179, 180, 181) but not all (182). In men, alcohol consumption over a 26-hour period affected neither melatonin nor the cortisol secretory diurnal variation (183, 184).

Autonomy of the adrenal

One feature of adrenocortical function that is hardly considered, in relation to addiction or anything else, is that mechanisms exist whereby the secretion of glucocorticoid appears to be regulated in part by local stimuli. CRH is notable among these. The relationship between the functions of hypothalamic CRH and CRH formed locally in the adrenal is currently obscure. That the adrenal gland of various species may secrete CRH from the medulla in response to splanchnic nerve stimulation has been shown, as has the direct stimulatory effect of CRH on corticosteroid secretion (185, 186, 187, 188). How does adrenal CRH vary with addiction? This is a topic for the future.

Conclusion

There is a clear pattern in the relationship of HPA activation to the development of addictive behaviours in response to quite different drugs. What is it they all have in common? Is there a unifying pathway that in so many cases leads to what may sometimes appear to be an addiction to the adrenal cortex and the secretion of glucocorticoids?

One point is becoming clear: CRH and POMC at different brain sites have clear functional links with the classical HPA (Fig. 1), and together, they may play similar roles in the adaptation that underlies addictive behaviour. They may be considered in the context of addiction as an expanded HPA, of which the terminal, and crucial, component is the adrenal cortex itself.

The evidence for the key importance of the adrenal cortex and glucocorticoids in behaviour and symptoms in drug withdrawal and reinstatement seems conclusive. Therapeutic control of glucocorticoid secretion or inhibition of glucocorticoid action at its receptor may be important future developments (148, 189) in what otherwise is a bleak therapeutic landscape (48, 189, 190, 191).

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

  • Received 24 May 2013
  • Accepted 31 May 2013
  • Made available online as an Accepted Preprint 31 May 2013

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

Front Psychiatry. 2013; 4: 72.

This article has been cited by other articles in PMC.

Abstract

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

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

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

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

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

What is Addiction?

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

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

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

Brain Reward Systems

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

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

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

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

Brain Stress Systems

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

Corticotropin-releasing factor

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

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

Dynorphin-κ opioid system

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

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

Dynamic Changes in Reward: Opponent Process

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

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

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

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

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

Neuroadaptations Responsible for Opponent Process

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Brain Stress Substrates that Mediate Drug Taking with Extended Access

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

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

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

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

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

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

NPY, compulsive drug seeking, and the extended amgydala

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

Corticotropin-releasing factor, stress, and the frontal cortex

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

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

Brain Stress Systems in Addiction: An Allostatic View

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

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

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

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

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

Conflict of Interest Statement

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

Acknowledgments

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

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Blockade of cocaine-induced increases in adrenocorticotrophic hormone and cortisol does not attenuate the subjective effects of smoked cocaine in humans (1999)

Behav Pharmacol. 1999 Sep;10(5):523-9.

Ward AS1, Collins ED, Haney M, Foltin RW, Fischman MW.

Abstract

Surgical or pharmacological ablation of the hypothalamic-pituitary-adrenal (HPA) axis reduces the discriminative stimulus and reinforcing effects of cocaine in laboratory rodents. We have recently reported that attenuation of cocaine-induced increases in cortisol does not modulate the subjective effects of smoked cocaine in humans.

To examine whether attenuation of HPA function at the pituitary level reduces the effects of cocaine in humans, eight 'crack' cocaine abusers were pre-treated with the synthetic glucocorticoid, dexamethasone (0 and 2 mg), 10 h before receiving cocaine. Three doses of smoked cocaine (0, 12 and 50 mg) were administered in counterbalanced order under each pre-treatment condition.

Dexamethasone alone increased heart rate and blood pressure, and completely abolished cocaine-induced adrenocorticotrophic hormone and cortisol release. Maximal heart rate following cocaine administration was significantly increased by dexamethasone.

However, the subjective effects of cocaine were not affected by dexamethasone pre-treatment. These results extend our earlier findings with humans, indicating that the role of the HPA axis in mediating the effects of cocaine is limited. These data are concordant with findings in non-human primates, but contrast with findings in laboratory rodents, thus underscoring the importance of validation of rodent models with laboratory studies in humans.

 

Brain Reward and Stress Systems in Addiction (2014)

Front Psychiatry. 2014; 5: 79.

Published online 2014 Jul 9. doi:  10.3389/fpsyt.2014.00079

PMCID: PMC4088186

This article has been cited by other articles in PMC.

Addiction to drugs and alcohol is a dynamic and multi-faceted disease process in humans, with devastating health and financial consequences for the individual and society at large. The recently released fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) combined the previously separate abuse and dependence classifications for licit and illicit drugs of abuse into a single syndrome called substance use disorder (SUD). This new definition includes diagnostic criteria that are largely overlapping with previous criteria (DSM-IV), and new diagnostic thresholds wherein physicians are charged with classifying the severity of an individual’s SUD based on the number of criteria met. More specifically, mild SUD requires that two to three symptoms be met, moderate SUD requires that four to five symptoms be met, and severe SUD requires that six or more symptoms be met. One notable addition to diagnostic criteria is craving, which can be defined broadly as a strong desire or urge to use drug/alcohol. Different classes of abused drugs can have different biological consequences and different co-morbidity risks, but SUDs are defined and diagnosed according to a single set of behavioral symptoms that are common to abuse of all drugs. These behavioral symptoms include compulsive drug use, loss of control in limiting drug intake, the emergence of a negative emotional state in the absence of the drug, and increased vulnerability to relapse triggered by stress or cues previously associated with drug availability. Each of these symptoms can be modeled to various degrees in animals, and animal models are particularly useful for exploring the underlying neurobiology of SUD and for identifying promising new targets for treatments aimed at curbing excessive drug and alcohol use in humans.

The main purpose of this Research Topic is to consolidate review and empirical articles by leaders in the addiction field that collectively explore the contribution of brain reward and stress systems in addiction. The transition to severe SUD is defined by neuroadaptations in brain circuits that, in the absence of drugs, are responsible for mediating behavioral and physiological processes that include motivation, positive and negative emotional states, nociception, and feeding. Chronic drug exposure during this transition promotes (1) within-system changes in neural circuits that contribute to the acute rewarding effects of the drug and (2) recruitment of both hypothalamic (neuroendocrine) and extra-hypothalamic brain stress systems.

Various biological and behavioral processes contribute to the propensity of an individual to use and abuse drugs and alcohol. For example, links are emerging between specific genetic profiles and diagnoses of SUDs. Furthermore, drug and alcohol abuse are highly co-morbid with other psychiatric conditions (e.g., anxiety disorders, major depressive disorder, schizophrenia, and personality disorders) that may precede or follow the development of drug use problems. Across different drugs of abuse, there are overlapping and dissociable aspects of the behavioral and neurobiological changes that define the transition to dependence. Even within a single drug of abuse, different people abuse drugs for various reasons; within a single individual, the reasons for drug abuse may change across the lifespan and the course of the disorder. The picture is further complicated by the fact that humans often abuse more than one drug concurrently.

This Research Topic begins with a review by Dr. George Koob, Ph.D., newly appointed Director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), that describes addiction as a disorder mediated by pathophysiological reductions in brain reward function and concurrent recruitment of brain stress circuits (1). Several of the articles that follow build on the idea that recruitment of brain stress systems [e.g., corticotropin-releasing factor (CRF) and glucocorticoids] is critical for promoting excessive drug and alcohol use. The remainder of this Research Topic is a collection of empirical and review articles that describe work aimed at unraveling the neurobiology of addiction to various drugs of abuse, and that ties this neurobiology with various current “hot topics” in the addiction research field (214).

The articles in this Research Topic address various points of current emphasis in the addiction research field. One such area is the idea of individual differences: it is gradually being accepted that addicts across and within drugs of abuse are not all the same, that individuals may arrive at the same phenotypic or diagnostic endpoint by different life paths and precipitating factors, that individuals exhibit different sets of co-morbidities (e.g., addiction and pain), and that therapeutic approaches and clinical trials may be more effective if tailored to subpopulations of addicts (i.e., pharmacogenetics). Also addressed in this set of articles is the notion that individual neurochemical systems may be critical for mediating not only abuse of more than one drug, but for mediating co-abuse of more than one drug in a single individual (e.g., the high rates of co-morbid smoking in individuals with alcohol use disorder). Another area of major social concern that is currently receiving much attention in the addiction research field is the drive to understand the long-term effects of adolescent drug and alcohol exposure on brain and behavior. It is generally accepted that early initiation of drug and alcohol use increases the risk for development of SUD and other psychiatric conditions later in life, and this may be due to the fact that the adolescent brain, because it is still developing, is particularly vulnerable to the effects of these substances.

Pre-clinical research utilizes a variety of animal models and rapidly advancing technological approaches to explore the underlying neurobiology of drug addiction. Several articles in this Research Topic describe commonly used genetic models (e.g., selective breeding animals for high alcohol preference) and more recently developed exposure models (e.g., nicotine vapor as a model for e-cigarettes and second-hand smoke) of addiction. These models can be combined with new technologies (e.g., optogenetics and chemogenetics) to examine the neurobiology of addiction in increasingly sophisticated ways, for example, the approach of isolating single brain regions is quickly being replaced by circuitry approaches, and intra-cranial delivery of drug solutions with “dirty” receptor binding and diffusion profiles are being replaced by highly controllable optical stimulation and designer drug techniques. Collectively, the articles presented here provide a snapshot of the current theoretical and experimental landscape in the addiction research field.

Conflict of Interest Statement

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

References

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Brain stress systems in the amygdala and addiction (2009)

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

Abstract

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

4. Extended amygdala: interface of stress and addiction

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

9. Brain stress systems and addiction

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

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

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

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

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

10. Summary and conclusions

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

Acknowledgments

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

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Chapter 3 – Stress psychobiology in the context of addiction medicine: from drugs of abuse to behavioral addictions (2016)

Volume 223, 2016, Pages 43–62

Neuroscience for Addiction Medicine: From Prevention to Rehabilitation - Constructs and Drugs

Abstract

In this chapter, we briefly review the basic biology of psychological stress and the stress response. We propose that psychological stress and the neurobiology of the stress response play in substance use initiation, maintenance, and relapse. The proposed mechanisms for this include, on the one hand, the complex interactions between biological mediators of the stress response and the dopaminergic reward system and, on the other hand, mediators of the stress response and other systems crucial in moderating key addiction-related behaviors such as endogenous opioids, the sympathetic-adrenal-medullary system, and endocannabinoids. Exciting new avenues of study including genomics, sex as a moderator of the stress response, and behavioral addictions (gambling, hypersexuality, dysfunctional internet use, and food as an addictive substance) are also briefly presented within the context of stress as a moderator of the addictive process.

Keywords Stress; Stress response pathways; Relapse; Emotions; Addictive behaviors; Hypothalamic-pituitary-adrenocortical axis; Sympathetic-adrenal-medullary response; Addictive behaviors; Cortisol


 

EXCERPTS:

Stress psychobiology in the context of addiction medicine from drugs of abuse to behavioral addictions

While a variety of stressors external to the addiction process may facilitate initial experimentation, chronic use, or relapse, the withdrawal and negative affect that accompanies withdrawal are in themselves an aversive and stressful experience (Kassel et al., 2007).Use in response to negative affect will result in negative reinforcement (removal of an aversive stimulus) which, in turn, increases the probability of subsequent use and, if repeated, chronic use. Positive reinforcement stems from the high or the pleasure experienced in response to use of an addictive substance

The current DSM 5 (American Psychiatric Association, 2014) has redefined the definition of addiction to include both substance abuse and dependence that occur along a natural continuum from mild to severe. Qualifying for a diagnosis under this new system the words “addiction” and “dependence” are avoided in favor of the more broad substance use disorders

Many of these attempts to cope with or eliminate the stressor during the resistance phase are either unsuccessful, or in the case of substance use in humans, harmful.

COMMON PATHWAYS BETWEEN STRESS AND ADDICTION

There is evidence that, in many ways, the dynamic neurophysiology of the stress response mirrors that of the neurophysiology evident in humans and animals who have been chronically exposed to drugs of abuse. For example, both stress and addiction share similar changes in behavior, similar neurophysiological changes in the HPA, LC–NE, autonomic, and eCB systems, and similar risk profiles (sex, psychopathology, etc.). Chronic social stress in animals and humans leads to increases in anxiety, negative affect, and changes in sleep and eating (Adam and Epel, 2007; Akerstedt, 2006; Chida and Hamer, 2008), all of which are common in persistent substance abuse. The same is true for disruptions in attention, concentration, memory, and decision making (Het et al., 2005). From a neurophysiological perspective, there are also many common pathways. As indicated above, both chronic social stress and chronic exposure to drugs of abuse such as morphine leads to changes in LC–NE functioning that appears to be dependent upon endogenous opioid functions (Chaijale et al., 2013; Curtis et al., 2012). In general, though there is some variability based on the chemistry of the abused substance, acute drug use also leads to increased HPA and SNS functioning in much the same way as stress (al’Absi et al., 2008; Fox et al., 2006; Hamidovic et al., 2010; Mick et al., 2013).

One common pathway that has received the most intense research attention is the role of dopaminergic reward pathways in the brain. As stated above, drugs of abuse heighten the activity of the HPA, SNS, and endogenous opioid systems in much the same way as chronic stress. The behavioral effects are, in turn, moderated by multiple neurobiological systems including the catecholamines: dopamine, NE, and serotonin (Salamone and Correa, 2013). The HPA and dopaminergic systems are interdependent (Boyson et al., 2014). Dopamine in particular has been linked to the reward properties of drug use. For example, pharmacological studies have shown that stress increases dopamine production via glucocorticoid receptor activation (Boyson et al., 2014). In particular, increased central CRF activity potentiates N-methyl-D-aspartate receptor activity which, in turn, results in increased dopaminergic transmission (Marinelli, 2007). Support for the role of HPA activation in increasing dopaminergic activity has been evident in studies using a variety of methodologies (Barrot et al., 2000; Graf et al., 2013). Through this research, critical CNS reward pathways and structures have identified including the ventral tegmental area, nucleus accumbens, and prefrontal cortex (Baik, 2013; Kringelbach et al., 2012; Lawrence and Brooks, 2014).

In addition to the dopaminergic reward pathway, both stress and drugs of abuse negatively impact the serotonergic pathway consisting of the raphe nucleus, striatum, nucleus accumbens, and the entire neocortex. The effects of altered serotonergic functioning are expressed as changes in mood, memory, sleep, and cognition; all of which are evident in chronic stress states and drug abuse (Kirby et al., 2011; Meerlo et al., 2008; Meneses, 2013)

Various physiological markers of stress predict relapse. For example, smokers who demonstrate an attenuated sympathetic and HPA stress response during the first 24 h of relapse have an increased risk of relapse status at 4 weeks postquit (al’Absi, 2006; al’Absi et al., 2004, 2005; Ceballos and al’Absi, 2006) as does heightened negative affect

Likewise, craving or distress-induced relapse is a powerful negative reinforcement for persistent smoking (Ahmed and Koob, 2005). Although this experience is psychologically stressful, the seemingly counterintuitive attenuated response of those who relapse appears to be related, at least in part, to CRF (Erb, 2007).

In addition to the HPA axis, catecholamines and glutamate within the nucleus accumbens and prefrontal cortex are induced by drug cues, drug use, and/or stress

Although we began this section using nicotine addiction as an example, it is important to point out that stress and abnormal cortisol responses have also been linked to relapse with other substances cessation attempts including cocaine, opiates, alcohol, amphetamines, and marijuana (Fox et al., 2013; Hamidovic et al., 2010; Higley et al., 2011; Sinha, 2011). With some abuse substances such as heroin, however, the cortisol response is elevated rather than attenuated, especially in response to drug paraphernalia cues (Fatseas et al., 2011). Regardless of the direction of the HPA changes, there is abundant evidence that drug use is related to dysregulation of the HPA axis, perhaps in concert with dysregulation in the emotional regulation, central reward, and executive function systems

STRESS AND BEHAVIORAL ADDICTIONS

For the first time, gambling disorder was added to the DSM 5 in 2013 due to its clear addictive behavior patterns (Hasin et al., 2013). If, as we have argued above, psychological stress is a key factor in the initiation, maintenance, and relapse for all addictions, then it would stand to reason that there should be evidence of such a stress and addiction relationship among all behavioral, emotional, cognitive, and physiological parameters of stress specific to gambling. This is, indeed, the case for many of these parameters. For example, reported psychosocial stresses such as divorce, marital strife, and a history of childhood abuse are more prevalent in samples of pathological gamblers (PGs) (Black et al., 2012). Higher life stress at the time of treatment is one of the strongest predicts PG relapse at 4 months posttreatment (Gomes and Pascual- Leone, 2014). Although baseline cortisol may not be elevated with gambling

disorder, there are negative correlations with the length of pathological gambling and cortisol, total gambling dysfunction, and distress over gambling behavior (Geisel et al., 2015). Further, gambling-related behaviors increase with experimental induction of a stress state, though not with all types of stressors (Steinberg et al., 2011). Early research indicates that stress physiology, as measured by the HPA, sympathetic, serotonergic, dopaminergic, and endogenous opioid systems, has been linked to gambling behaviors, maintenance, and relapse (Blanchard et al., 2000; Campbell-Meiklejohn et al., 2011; van den Bos et al., 2009). For PGs, basal circulating NE, EPI, and dopamine are elevated and the act of gambling is an arousal state (Meyer et al., 2004). In contrast to basal levels or gambling behaviors, the cortisol response to gambling cues may be absent for PGs but not recreational gamblers

(Paris et al., 2010a,b). Finally, neuroimaging studies indicate that, like alcohol addiction, pathological gambling is associated with abnormalities in the anterior cingulate, ventral striatum, and prefrontal cortices (Koehler et al., 2013). Other behaviors with addictive qualities (persistent and dysfunctional use or behavior leading to clinically significant impairment or distress) include hypersexuality, internet use disorder, and noneating disordered excessive eating (AKA “food addiction”). While each of these have not yet risen to the level of inclusion in the DSM 5 as a substance use disorder, there is some recognition that each of these have in common an escalating pattern of use leading to dysfunction. Further, early evidence exists of a link between these potential behavioral addictions (purported sex addiction and internet use disorder) and dopamine, self-reported stress, or the HPA axis dysregulation (Farre et al., 2015; Hou et al., 2012). Finally, there is currently a large debate on whether or not there is a “food addiction” or “eating addiction” that is distinct from the traditional eating disorders of anorexia or bulimia exists (Rogers and Smit, 2000). Although still quite controversial, those who support the notion of a food addiction point to its vulnerability to stress and the dopaminergic reward system as supporting evidence of its distinction from other eating disorders (Adam and Epel, 2007; Volkow et al., 2013).

 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Corticotropin releasing factor type2 receptor and corticotropin releasing factor binding protein coexist in rat ventral tegmental area nerve terminals originated in the lateral hypothalamic area (2015)

Eur J Neurosci. 2015 Oct 27. doi: 10.1111/ejn.13113.

Slater PG1, Noches V1, Gysling K1.

Abstract

There is significant functional evidence showing that corticotropin releasing factor type-2 receptor (CRF2 R) and corticotropin releasing factor-binding protein (CRF-BP) regulate glutamatergic synapses onto ventral tegmental area dopaminergic neurons. It has been shown that CRF requires CRF-BP to potentiate N-methyl-D-aspartate receptors in dopaminergic neurons through CRF2 R, and that increases glutamate release in cocaine-treated rats through the activation of CRF2 R only by agonists with high affinity to CRF-BP. Furthermore, this CRF-mediated increase in ventral tegmental area glutamate is responsible for stress-induced relapse to cocaine-seeking behavior.

However, there is lack of anatomical evidence to explain the mechanisms of CRF actions in ventral tegmental area.

Thus, we studied whether CRF2 R and CRF-BP are expressed in ventral tegmental area nerve terminals, using a synaptosomal preparation devoid of postsynaptic elements.

Our results show that both proteins are co-expressed in glutamatergic and GABAergic ventral tegmental area synaptosomes. A main glutamatergic input to the ventral tegmental area that has been associated to addictive behavior is originated in the lateral hypothalamic area. Thus, we focused our study in the lateral hypothalamic area-ventral tegmental area input using orexin as a marker of this input.

Our results show that CRF2 R and CRF-BP mRNA and protein are expressed in the lateral hypothalamic area and that both proteins are present in orexin-positive ventral tegmental area synaptosomes.

Our results showing that CRF2 R and CRF-BP are expressed in the lateral hypothalamic area-ventral tegmental area input give anatomical support to suggest that this input plays a role in stress-induced relapse to cocaine-seeking behavior.

 

Corticotropin-releasing factor in the nucleus accumbens shell induces swim depression, anxiety, and anhedonia along with changes in local dopamine/acetylcholine balance (2012)

Neuroscience. 2012 Mar 29;206:155-66. doi: 10.1016/j.neuroscience.2011.12.009. Epub 2012 Jan 5.

Chen YW1, Rada PV, Bützler BP, Leibowitz SF, Hoebel BG.

Abstract

The nucleus accumbens shell (NAcS) has been implicated in controlling stress responses through corticotropin-releasing factor (CRF). In addition to studies indicating that CRF in the NAcS increases appetitive motivation, there is indirect evidence suggesting that NAcS CRF may also cause aversive responses and that these behaviors may be mediated through local dopamine (DA) and acetylcholine (ACh) systems. To provide a direct test of this hypothesis, we used male Sprague-Dawley rats with implanted cannulas aimed at the NAcS. Experiment 1 showed local CRF injection (10 or 50 ng/side) to increase immobility in the forced swim test and a CRF antagonist D-Phe-CRF ((12-41)) to attenuate this depressive-like behavior. In Experiment 2, injection of CRF (250 ng/side) also decreased the rats' preference for sucrose, while in Experiment 3, CRF (50 or 250 ng/side) induced anxiety-like behaviors in an elevated plus maze and open field. These same doses of CRF in Experiment 4 failed to alter the rats' locomotor activity, indicating that these behavioral changes were not caused by deficits in activity. In Experiment 5, results from in vivo microdialysis revealed that CRF in the NAcS markedly increased local extracellular ACh, while also producing a small increase in DA. These results show that NAcS CRF can generate a variety of aversive behaviors, including swim depression, anhedonia, and anxiety, in addition to approach behavior. They suggest that these behaviors may occur, in part, through enhanced activation of ACh and DA in the NAcS, respectively, supporting a role for this brain area in mediating the dual effects of stress.

Cortisol Secretion Patterns In Addiction And Addiction Risk (2006)

Int J Psychophysiol. Author manuscript; available in PMC 2008 Feb 27.

William R. Lovallo*

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Abstract

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

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

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1. Introduction

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

1.1. Diurnal and stress-related regulation of the HPA

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

Fig. 1

Fig. 1

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

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

Our understanding of cortisol responses to psychological stress was increased by the discovery that cortisol has a widespread system of receptors above the hypothalamus. These are found in the hippocampus, the limbic system, and the prefrontal cortex (McEwen et al., 1968; Sanchez et al., 2000). The distribution of these receptors argues strongly that higher brain centers play a role during the psychological stress response and cause responses of the HPA. In fact, during periods of psychological distress, cortisol's diurnal pattern is overridden by signals to the hypothalamus that originate in the limbic system. The signals arise in the amygdala and the bed nuclei of the stria terminalis, structures that are activated by conditioned and unconditioned stimuli and that convey information having survival value (Amaral et al., 1992; Halgren, 1992; LeDoux, 1993). The amygdala therefore stands at the center of a neural network that generates approach and avoidance reactions to innate and learned stimuli (Rolls and Stringer, 2001). Outputs from the amygdala and bed nuclei interact with nearby structures, s