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Volume 34 Issue 4

Resilience to Meet the Challenge of Addiction: Psychobiology and Clinical Considerations

Tanja N. Alim, M.D.; William B. Lawson, M.D.; Adriana Feder, M.D.; Brian M. Iacoviello, Ph.D.; Shireen Saxena, M.S.; Christopher R. Bailey; Allison M. Greene, M.S.; and Alexander Neumeister, M.D.

Tanja N. Alim, M.D., is an assistant professor and William B. Lawson, M.D., is a professor and chair of the Department of Psychiatry, both at the Department of Psychiatry and Behavioral Sciences, Howard University, Washington, DC.

Adriana Feder, M.D., is an assistant professor; Brian M. Iacoviello, Ph.D., is a postdoctoral fellow; and Shireen Saxena, M.S., Christopher R. Bailey, and Allison M. Greene, M.S., are research associates; all at the Mood and Anxiety Disorders Program, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York.

Alexander Neumeister, M.D., is a professor in the Department of Psychiatry and Radiology, New York University Langone Medical Center, New York, New York.


    Acute and chronic stress–related mechanisms play an important role in the development of addiction and its chronic, relapsing nature. Multisystem adaptations in brain, body, behavioral, and social function may contribute to a dysregulated physiological state that is maintained beyond the homeostatic range. In addition, chronic abuse of substances leads to an altered set point across multiple systems. Resilience can be defined as the absence of psychopathology despite exposure to high stress and reflects a person’s ability to cope successfully in the face of adversity, demonstrating adaptive psychological and physiological stress responses. The study of resilience can be approached by examining interindividual stress responsibility at multiple phenotypic levels, ranging from psychological differences in the way people cope with stress to differences in neurochemical or neural circuitry function. The ultimate goal of such research is the development of strategies and interventions to enhance resilience and coping in the face of stress and prevent the onset of addiction problems or relapse.

    Evidence from different disciplines suggests that acute and chronic stress–related mechanisms play an important role in both the development and the chronic, relapsing nature of addiction (Baumeister 2003; Baumeister et al. 1994; Brady and Sinha 2005). Stress is defined as the physiological and psychological process resulting from a challenge to homeostasis by any real or perceived demand on the body (Lazarus and Fokman 1984; McEwen 2000; Selye 1976). Stress often induces multisystem adaptations that occur in the brain and body and affect behavioral and social function. The resulting dynamic condition is a dysregulated physiological state maintained beyond the homeostatic range. This definition and conceptualization of stress was further developed to explain the chronic abuse of substances and comfort foods and has been studied in the context of behavioral addiction (i.e., pathological gambling) (Dallman et al. 2005; Koob and Le Moal 1997; Koob 2003). Persistent challenges to an organism through chronic substance use may ultimately lead to an altered set point across multiple systems. This hypothesis is consistent with evidence that suggests adaptations in brain reward and stress circuits, and local physiology (e.g., energy balance) can contribute to addictive processes. Cravings or urges, decreases in self-control, and a compulsive engagement in unhealthy behaviors each characterize patients with addiction (Dallman et al. 2005; Kalivas and Volkow 2005; Koob et al. 2004; Sinha 2001). Alternatively, a person’s ability to successfully cope with high stress is reflected in adaptive physiological and psychological responses (Charney 2004; MacQueen et al. 2003).

    Resilience, defined as the absence of psychopathology despite exposure to high stress, can be studied by examining interindividual differences in stress responsivity across an organism’s various types (i.e., at multiple phenotypic levels). Responsivity ranges from psychological differences in the way individuals cope with stress to differences in neurochemical or neural circuitry function (Cicchetti and Blender 2006). Variability within the genetic makeup and quality of early-life experience, as well as interactions between the two, are known to contribute to differences in stress resilience (Enoch 2010; Heim and Nemeroff 2001). Genetic influences can stem from gene–environment interactions, changes in gene expression influenced by the environment (i.e., epigenetic changes), or variation within the actual genetic code. Some examples of genetic influences on resilience include variability in the genes involved in the body’s stress response (i.e., those controlling the hypothalamic–pituitary–adrenal [HPA] axis). These include those coding for the corticotropin-releasing factor (CRF) type 1 receptor or the glucocorticoid receptor (GR) (which cortisol can activate) as well as the serotonin transporter cathecol-O-methyltransferase (COMT), neuropeptide Y (NPY), and brain-derived neurotrophic factor (BDNF) genes (Feder et al. 2009) Genetic variation in the gene encoding the CRH1 receptor was found to moderate the impact of stress, for example, among adolescents engaging in heavy drinking (Blomeyer et al. 2008; Schmid et al. 2010). This gene-by-environment interaction predicted the initiation of drinking in adolescence as well as progression to heavy drinking by young adulthood (Schmid et al. 2010). The following sections highlight resilient responses to stress in studies in which stress was identified as an important factor contributing to the neurobiology of alcohol dependence.

    Psychosocial Factors Associated With Resilience

    Early studies of children exposed to adversity (Masten 2001; Masten and Coatsworth 1998; Rutter 1985) as well as more recent studies in resilient adults (Ahmad et al. 2010; Alim et al. 2008; Bonanno 2004) have identified a range of psychosocial factors associated with successful adaptation to stressful or traumatic events. For example, the ability to simultaneously experience both positive and negative emotions when confronted with a high-stress situation increases flexibility of thinking and problem solving and can buffer individuals from developing stress-induced adverse consequences (Fredrickson 2001; Ong et al. 2006). Likewise, optimism has been associated with resilience to stress-related disorders, including alcohol use disorders (Ahmad et al. 2010; Alim et al. 2008).

    Unlike personality characteristics associated with increased risk for substance use disorders (e.g., impulsivity, novelty seeking, and negative emotionality), positive emotionality, the tendency to experience positive mood frequently, was found to be associated with resilience to substance use in a large longitudinal study of public school students followed from late childhood through midadolescence (Wills et al. 2001).

    In this study, positive emotionality was found to buffer the effects of parent– child conflict and of parental and peer substance use on adolescent substance use. The ability to focus attention on performing and completing tasks was identified as a protective factor against substance use (Wills et al. 2001). The ability to focus attention might relate to the capacity to cope by planning and problem solving in times of stress, both types of coping styles characteristic of resilient individuals (Southwick et al. 2005).

    Veenstra and colleagues (2007) examined the impact of coping style on alcohol use in response to stressful life events in a sample of 1,608 men and 1,645 women drawn randomly from the Dutch Lifestyle and Health Study (Veenstra et al 2007). Individuals who scored high on emotion coping, a coping style focused on feelings and emotional content to cope with stress, used more alcohol when experiencing a negative life event, compared with those who scored low on emotion coping. Alcohol use in times of stress did not vary by cognitive or by action coping, but the study found that cognitive coping and having more social contacts was linked to lower alcohol use in general. Another study of more than 1,300 adult drinkers in the general population from a New York county found stress-induced drinking in a subset of men (but not women) who scored high on avoidance coping and on positive expectancy from alcohol (Cooper et al. 1992). Men with low-avoidance coping and low expectancy from alcohol, on the other hand, actually showed a negative relationship between stressful life events and alcohol use. Of note, low avoidance coping has been linked to stress resilience in general, in several other studies (Alim et al. 2008; Carver et al. 1997).

    Neurochemistry of Resilience

    “Allostasis” refers to the dynamic process through which the body adapts to daily stressors and maintains homeostasis (Sterling and Eyer 1988). Sudden stressful events trigger the release of the “flight-or-fight” hormones (i.e., catecholamines) and other stress hormones in the brain, preparing the organism to cope with stress and avert harm. This process is mediated by a stress circuit (see figure 1), which is consistently implicated in stress-related disorders such as mood and anxiety disorders and addictive disorders. Interindividual variability in stress resilience results from differences in the coordinated stress response. This response comprises the function and interactions of numerous hormones, neurotransmitters, and neuropeptides, some of which are discussed below.

    Norepinephrine (NE) and dopamine (DA) are the principle chemical messengers employed in central and peripheral sympathetic synapses, and the human NE transporter rapidly clears NE and DA from the synaptic cleft via efficient transport systemattenuating signaling, recycling 90 percent of these synaptic monoamines. NE neurons innervate nearly all parts of the neuroaxis, with the locus coeruleus (LC) being responsible for most of the NE in the brain.
    Figure 1 Norepinephrine (NE) and dopamine (DA) are the principle chemical messengers employed in central and peripheral sympathetic synapses, and the human NE transporter rapidly clears NE and DA from the synaptic cleft via efficient transport systemattenuating signaling, recycling 90 percent of these synaptic monoamines. NE neurons innervate nearly all parts of the neuroaxis, with the locus coeruleus (LC) being responsible for most of the NE in the brain. NE exerts neuromodulatory effects on the cellular activity of post-synaptic target neurons in many brain circuits, thereby moderating synaptic transmission in target circuits including the thalamus, prefrontalcortex (PFC), ventral striatum (via PFC), and amygdala, which have been implicated in substance use disorders. The widespread and divergent anatomical organization positions the NE system to be involved in widely varying functions including responses to stress, which alters both the electrophysiological activity of NE neurons in the LC and the release of NE in the terminal regions of these cells, as well as crucial cognitive functions, including attention and arousal. NE mediates many of the adaptive and maladaptive consequences of stress exposure, implicating this system in a variety of abnormal behaviors including alcohol dependence.

    HPA Axis

    The HPA axis is a system regulated by a complex negative-feedback system. CRF, released by the hypothalamus in response to stress, triggers the release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary gland. This process leads to the synthesis and release of cortisol by the adrenal cortex. Cortisol secretion acutely facilitates cognitive, metabolic, immunologic, and behavioral adaptations to stress. It also results, however, in “allostatic overload” when stress becomes chronic or overwhelming (McEwen 2003). Resilience is maintained when the stress response is both activated and terminated efficiently. The adaptive responses of the HPA axis are thought to involve an optimal balance of the cortisol-binding receptors GR and mineralocorticoid receptor (de Kloet et al. 2005, 2007).

    Studies showing lower plasma levels of ACTH but not cortisol in men with a family history of alcoholism (Dai et al. 2007; Gianoulakis et al. 2005) suggest that HPA axis dysfunction might predate the onset of alcoholism. Long-term alcohol abuse is associated with increased extrahypothalamic CRF signaling and dampened HPA axis responsivity (Richardson et al. 2008). Increases in extrahypothalamic CRF contribute to negative emotional states during abstinence, increasing risk for relapse (Koob and Le Moal 2008). In a recent study, researchers asked alcoholics who had been abstinent for 1 month to imagine a relaxing situation of their choice while listening to a previously recorded audiotape of this situation. A greater cortisol-to-corticotropin ratio (i.e., higher adrenal sensitivity) during this relaxed state was found to predict a shorter time to alcohol relapse, thus suggesting that new treatments aimed a decreasing adrenal sensitivity could reduce relapse rates (Sinha et al. 2011).


    During the acute stress response, the hormone norepinephrine (NE) is released through direct projections from the brain site where NE is synthesized (i.e., locus coeruleus) and other brain stem nuclei (i.e., structures that act as transit points for brain signals) into the amygdala, hippocampus, nucleus accumbens, prefrontal cortex (PFC), and other brain areas mediating emotional responses. Several studies have linked abnormal regulation of brain NE systems to stress disorders (Krystal and Neumeister 2009; O’Donnell et al. 2004). As drug dependence develops, levels of the neurotransmitter dopamine decrease and the NE stress system in the brain is activated, contributing to “stress-like states” and increased vulnerability to stressors during periods of abstinence (Koob and Le Moal 2008). In combination with CRF, NE also might contribute to the consolidation of emotional memories associated with drug use in the amygdala (Koob et al. 2009).

    Stress resilience may be enhanced through the regulation of NE system responsiveness, which is mediated through effects on the NE transporter on catecholamine receptors (i.e., α2 adrenoreceptors), as well as interactions between the NE and other neurobiologic systems, such as the dopamine and serotonin systems (Krystal and Neumeister 2009). For example, animal studies have shown that PFC NE nerve cell projections (i.e., axons) have a latent capacity to enhance synthesis and recovery of transmitter, which might underlie the capacity to adapt to stress (Miner et al. 2006). This mechanism deserves further study in humans with positron emission tomography (PET), which uses positron-emitting radiotracers to show where and how compounds act in the brain (Ding et al. 2005). Other targets include the α2a and α2c receptors, which have complementary roles in the regulation of stress responses (Small et al. 2000). Yohimbine, a drug that blocks the α2 receptors (i.e., a receptor antagonist), increases alcohol self-administration and induces reinstatement of alcohol seeking (Le et al. 2005; Marinelli et al. 2007). The recent finding that an α2c receptor polymorphism (Del322-325) reduces feedback inhibition of sympathetic NE release (Neumeister et al. 2005) as well as evidence from studies in mice bred to have an inactivated α2c receptor (i.e., knockout mice) (Sallinen et al. 1999), suggest that interventions targeting this receptor might modulate stress and anxiety responses.


    The serotonin (5-HT) system, which consists primarily of neurons from the dorsal raphe nuclei that project widely throughout the brain (including the amygdala, ventral striatum, and PFC), is involved in the regulation of stress and anxiety. Serotonin has an important role in promoting neuroplasticity in the central nervous system, both during development and in adulthood. Serotonin also regulates the neurochemical effects of drugs of abuse, including alcohol, and is involved in modulating impulsivity, known to increase risk for alcohol and drug abuse (Kirby et al. 2011). The 5-HT system is itself modulated by drugs of abuse. For example, alcohol administration elevates 5-HT levels in the nucleus accumbens, ventral tegmental area (VTA), amygdala, and hippocampus, an effect that is more pronounced in alcohol-preferring rats. Reduced activity of the 5-HT system might contribute to depression during withdrawal and increase vulnerability to relapse (Kirby et al. 2011). In studies of macaques, differential function of the 5-HT system in interaction with early life stress was found to affect alcohol consumption: peer-reared female macaques with a specific variant (i.e., the l/s genotype) of the serotonin transporter polymorphism showed higher levels of ethanol preference and increased consumption over time (Barr et al. 2004).

    The 5-HT system is extremely complex, including at least 14 receptor subtypes. Of these receptors, the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptors are well understood through research on anxiety regulation in both animals and humans (Krystal and Neumeister 2009). The 5-HT1A receptor is thought to counteract the deleterious effects of 5-HT2A receptor activation (i.e., the disruption of brain cell creation), mediated by increased release of the neurotransmitter glutamate and direct glucocorticoid effects (Hoebel et al 2007). Restrained function of another 5-HT receptor, 5HT1B, might be central to resilient stress responses by enhancing synaptic availability of 5-HT in the amygdala and other cortical regions as well as promoting dopamine release in the ventral striatum (Clark and Neumaier 2001; Krystal and Neumeister 2009; Sari 2004) (see figure 2).

    Alterations in serotonin 1B receptor (5HT1BR) function might contribute to alcohol dependence by influencing not only serotonin (5HT) input to the ventral striatum via the receptors’ role as 5HT terminal autoreceptors,<sup>1</sup> but also dopaminergic input to the striatum via the role of these receptors as heteroreceptors<sup>2</sup> on GABA terminals within the ventral tegmental area, and glutamatergic activity within the ventral striatum via heteroreceptors on corticofugal projections.
    Figure 2 Alterations in serotonin 1B receptor (5HT1BR) function might contribute to alcohol dependence by influencing not only serotonin (5HT) input to the ventral striatum via the receptors’ role as 5HT terminal autoreceptors,1 but also dopaminergic input to the striatum via the role of these receptors as heteroreceptors2 on GABA terminals within the ventral tegmental area, and glutamatergic activity within the ventral striatum via heteroreceptors on corticofugal projections.

    1 Autoreceptor: A site on a neuron that binds the neurotransmitter released by that neuron, which then regulates the neuron’s activity.
    2 Heteroreceptor: A site on a neuron that binds a modulatory neuroregulator other than that released by the neuron.

    The role of this receptor subtype in addiction disorders recently was studied in humans. The report demonstrated that alcohol dependence in humans, like in rodent models, is associated with increased levels of ventral striatal 5-HT1B receptors (Hu et al. 2010). Additional research is necessary to understand the complex function of the 5-HT system. However, these findings suggest possible novel targets for the treatment of stress-related disorders and, most important, addiction disorders.


    Dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain project to the nucleus accumbens and other limbic areas to form the mesolimbic dopamine system, the most studied reward circuit. Dopamine neurons are activated in response to reward or the expectation of reward, and generally are inhibited by aversive stimuli. Dopamine signaling is central to the onset of addiction, as well as to the transition to dependence in interaction with other neurotransmitter systems (Ross and Peselow 2009). Drugs of addiction trigger large but brief increases in extracellular dopamine in the nucleus accumbens. Over time, chronic drug use downregulates dopamine receptors and dopamine release, leading to decreased sensitivity to natural rewards, such as food and sex, and leading also to further drug use (Volkow et al 2010).

    Although findings from animal studies suggest that early-life stress can lead to long-lasting changes in gene expression in the mesolimbic dopamine pathway, ultimately increasing vulnerability to addictive disorders, not all individuals with a history of childhood abuse develop addictive or other disorders, thereby stressing the role of protective factors such as genetic variants conferring resilience (Enoch 2010).

    Findings from several studies suggest that higher dopamine D2 receptor availability in the striatum might promote resilience to alcohol use disorders. In a study of unaffected members of alcoholic families, higher striatal dopamine D2 receptor availability was associated with higher positive emotionality, discussed above as a protective factor against alcohol use disorders (Volkow et al 2006). Other studies found that higher striatal dopamine D2 receptor availability was associated with resistance to the reinforcing effects of stimulants in healthy volunteers (Volkow et al. 1999, 2002) and in rats (Thanos et al. 2008).


    NPY, a 36–amino acid peptide, is widely distributed in the brain. NPY has anxiety-reducing properties in rodents and is thought to enhance resilience to stress in humans (Feder et al. 2009; Morgan et al. 2000). Evidence from animal and human studies suggests that NPY has a key role in regulating alcohol intake, dependence, and withdrawal. Mice genetically modified to overexpress NPY consume less alcohol (Thiele et al. 1998), and administration of NPY into the cerebral ventricles of the brain (i.e., intracerebroventricular infusion) reduces alcohol consumption in alcohol-preferring rats (Thorsell 2007). Infusion of NPY into the central nucleus of the amygdala has been shown to normalize both anxiety behaviors and alcohol intake, suggesting that NPY might work by modulating anxiety responses (Zhang et al. 2010). In rhesus macaques exposed to early life stress, and in human studies, certain NPY gene polymorphisms are associated with differential susceptibility to alcohol or cocaine dependence (Koehnke et al. 2002; Lindell et al. 2010; Mottagui- Tabar et al. 2005; Wetherill et al. 2008).


    An emerging body of evidence suggests an important role for the endogenous cannabinoid (eCB) system and specifically the CB1 receptor in alcohol-related behaviors (for review, see Basavarajappa 2007). To date, however, only peripheral measures of eCB function have been collected in living humans with alcohol dependence (AD) (Mangieri et al. 2009), and no human in vivo data on the potentially critical role of the brain CB1 receptor in AD have been collected yet. At a neurobiological level, studies show impairments in decision making in alcohol-dependent patients (Dom et al. 2006), which is associated with altered functions in a cortico-limbic- striatal circuit, including the amygdala, hippocampus, anterior cingulate cortex, insula, and the ventral striatum. Three sets of factors are thought to be responsible for high alcohol relapse rates. First, individual differences in the positive, reinforcing properties of alcohol are known to increase risk of alcoholism and possibly alcohol relapse (Schuckit and Smith 1996). Second, stimuli previously associated with alcohol use and its physiological and subjective effects become paired with alcohol and are thought to serve as “conditioned cues” that can increase alcohol craving and subsequent alcohol use (O’Brien et al. 1998). Finally, stress has been found to increase the risk of alcohol relapse (Brown et al. 1990; Miller et al. 1996; Sinha 2001). All three factors can be linked to the eCB system and its attending CB1 receptor and increasing evidence derived from animal studies suggests a role of the eCB system in alcohol-related behaviors (Vinod and Hungund 2006).

    Such research suggests that upregulation of CB1 receptor–mediated G-protein signaling in a brain circuit that mediates AD susceptibility (involving the amygdala, hippocampus, ventromedial prefrontal cortex, insula, and ventral striatum) (Sullivan and Pfefferbaum 2005) might contribute to the increased alcohol consumption in patients with chronic AD. For example, CB1 inactivation (Hungund et al. 2003; Naassila et al. 2004; Poncelet et al. 2003; Thanos et al. 2005) and pharmacological manipulation of CB1 receptor function (Femenia et al. 2010; Maccioni et al.; Maccioni et al. 2008; Malinen and Hyytia 2008) result in reduced voluntary alcohol intake. In addition, administration of an agent that binds to the CB1 receptor (i.e., a CB1 receptor agonist) (Colombo et al. 2002; Gallate et al. 1999; Vinod et al. 2008b) enhances alcohol consumption.

    In contrast, acute, short-term alcohol intoxication is associated with elevated eCB levels (Basavarajappa et al. 2006; Blednov et al. 2007; Vinod et al. 2008a), reduced activity of the enzyme fatty acid amide hydrolase (FAAH), and reduced CB1 receptor–mediated G-protein signaling (Vinod et al. 2011). This mediates the activation of the mesolimbic dopaminergic system (Cheer et al. 2007; Hungund et al. 2003 ), which has been extensively studied in alcohol dependence. Evidence suggests a functional interaction between these systems, which might be associated with the reinforcing effects of alcohol and therefore may be an important mechanism in the etiology of alcohol dependence. Findings in animal studies recently have stimulated interest in the therapeutic potential of enhancing eCB signaling, with research in humans having just begun (Hill et al. 2009). However, an accumulating body of evidence suggests that the eCB system, and in particular its attending CB1 receptor, provides novel leads for treatment development in alcohol dependence (Bailey and Neumeister 2011).

    Behavioral Interventions to Enhance Resilience

    To date, most studies on resilience have been conducted in clinical populations with people exposed to traumatic life events as a prototype of stress-related disorders. However, these studies also can inform the development and implementation of behavioral interventions to address alcohol dependence. This is a critical application because the ultimate goal of research attempting to delineate a range of psychological, neurochemical, and brain circuitry mechanisms underlying resilience is the development of strategies and interventions aimed at enhancing resilience in the face of stress, which is of particular relevance for people struggling with alcohol dependence.

    As related to alcohol dependence, improving resilience would influence cognitive and emotional control in the face of stress, resulting in the ability to weather cravings without using alcohol, mindfulness to be aware of impulsive behavior and potentially avoid impulsive behaviors associated with alcohol use, and the development of prosocial behavior and interpersonal relations that could serve to support the individual in the face of stress and prevent alcohol use. Several cognitive and behavioral interventions have been developed in an effort to develop these capacities. These interventions, which include various forms of cognitive and behavioral psychotherapies (Butler et al. 2006; Marlatt 2001), mindfulness-based stress reduction (e.g., Astin 1997; Shapiro et al. 1998; Teasdale et al. 2000) and other therapeutic approaches, aim to help prevent the onset or minimize the extent of alcohol use behaviors. In addition, therapeutic approaches based on positive psychology might also help promote psychological resilience (e.g., Seligman and Csikszentmihalyi 2000) and are currently being evaluated for their effectiveness in addressing alcohol dependence.

    Taken together, interventions aimed at enhancing resilience to stress that focus on developing cognitive reappraisal skills, fostering mindfulness, and facilitating social interaction that results in enhanced social support could be particularly effective in helping people cope with stress and preventing the onset of alcohol use problems or relapse. Indeed, cognitive–behavioral models of addiction and relapse treatment such as those provided by Marlatt and colleagues (e.g., Marlatt 2001) highlight the role of experiencing negative affect as a primary trigger for using alcohol and relapsing. Mindfulness skills can be particularly useful in helping an individual cope with negative affect in the moment without resorting to the use of substances. Moreover, the attributions that individuals make upon relapsing (whether the attribution for use is internal and stable: “I just can’t handle stress and I’m bound to keep using”—versus external and unstable: “This was really stressful and difficult to deal with, and I decided to take the easy route this time”) can influence whether the relapse develops into a full-blown relapse or remains an isolated event. Cognitive reappraisal of these situations and the attributions that individuals make of their alcohol use can thus be of great importance in developing resilience in the treatment of alcohol use disorders.

    Conclusions and Future Directions

    Despite extensive research and knowledge regarding their serious adverse consequences, addiction disorders continue to contribute to the top preventable causes of death and morbidity in the United States (Centers for Disease Control and Prevention 2003). The mechanisms underlying the persistent and compulsive engagement in these behaviors remain poorly understood. Based on previous evidence, researchers have hypothesized that the chronic nature of addiction disorders is rooted in the neurotoxic effects of stress on the brain. These effects undermine the neuroplasticity within networks required for the recovery process to take place. As a result, mechanisms of resilience are crucial to the understanding of neuroadaptive potential and its behavioral consequences. This is an important topic of current research, which stands at a unique crossroad in the study of addiction disorders. The explosion in the field of molecular and cellular neuroscience calls for interdisciplinary, collaborative team-based approaches.

    A greater understanding of the neurobiology of stress and resilience, as well as its implications on the neuro­biology of addictions, is crucial to the prevention of such disorders and to the development of evidence-based treatment strategies.


    This paper was supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) through the following awards: R21 AA–018329, RL1 AA–017540, and RL1 AA–017540–S1.


    Ahmad, S.; Feder, A.; Lee, E.J.; et al. Earthquake impact in a remote South Asian population: Psychosocial factors and posttraumatic symptoms. Journal of Traumatic Stress 23(3):408–412, 2010. PMID: 20564375

    Alim, T.N.; Feder, A.; Graves, R.E.; et al. Trauma, resilience, and recovery in a high-risk African-American population. American Journal of Psychiatry 165(12):1566–1575, 2008. PMID: 19015233

    Astin, J.A. Stress reduction through mindfulness meditation: Effects on psychological symptomatology, sense of control, and spiritual experiences. Psychotherapy and Psychosomatics 66(2):97–106, 1997. PMID: 9097338

    Bailey, C.R., and Neumeister, A. Cb1 receptor-mediated signaling emerges as a novel lead to evidence-based treatment development for stress-related psychopathology. Neuroscience Letters 502(1):1–4, 2011. PMID: 21787837

    Barr, C.S.; Schwandt, M.L.; Newman, T.K.; and Higley, J.D. The use of adolescent nonhuman primates to model human alcohol intake: Neurobiological, genetic, and psychological variables. Annals of the New York Academy of Sciences 1021:221–233, 2004. PMID: 15251892

    Basavarajappa, B.S. The endocannabinoid signaling system: A potential target for next-generation therapeutics for alcoholism. Mini Reviews in Medicinal Chemistry 7(8):769–779, 2007. PMID: 17692039

    Basavarajappa, B.S.; Yalamanchili; R.; Cravatt, B.F.; et al. Increased ethanol consumption and preference and decreased ethanol sensitivity in female FAAH knockout mice. Neuropharmacology 50(7):834–844, 2006. PMID: 16448676

    Baumeister, R.F. Ego depletion and self-regulation failure: A resource model of self-control. Alcoholism: Clinical and Experimental Research 27(2):281–284, 2003. PMID: 12605077

    Baumeister, R.F.; Heatherton, T.F.; and Tice, D.M. Losing Control: How and Why People Fail at Self-Regulation. San Diego, CA: Academic Press, 1994.

    Beauregard, M. Mind does really matter: Evidence from neuroimaging studies of emotional self-regulation, psychotherapy, and placebo effect. Progress in Neurobiology 81(4):218–236, 2007. PMID: 17349730

    Blednov, Y.A.; Cravatt, B.F.; Boehm, S.L., 2nd; et al. Role of endocannabinoids in alcohol consumption and intoxication: Studies of mice lacking fatty acid amide hydrolase. Neuropsychopharmacology 32(7):1570–1582, 2007. PMID: 17164820

    Blomeyer, D.; Treutlein, J.; Esser, G.; et al. Interaction between CRHR1 gene and stressful life events predicts adolescent heavy alcohol use. Biological Psychiatry 63(2):146–151, 2008. PMID: 17597588

    Bonanno, G.A. Loss, trauma, and human resilience: Have we underestimated the human capacity to thrive after extremely aversive events? American Psychologist 59(1):20–28, 2004. PMID: 14736317

    Brady, K.T., and Sinha, R. Co-occurring mental and substance use disorders: The neurobiological effects of chronic stress. American Journal of Psychiatry 162(8):1483–1493, 2005. PMID: 16055769

    Brown, S.A.; Vik, P.W.; McQuaid, J.R.; et al. Severity of psychosocial stress and outcome of alcoholism treatment. Journal of Abnormal Psychology 99(4):344–348, 1990. PMID: 2266207

    Butler, A.C.; Chapman, J.E.; Forman, E.M.; and Beck, A.T. The empirical status of cognitive-behavioral therapy: A review of meta-analyses. Clinical Psychology Review 26(1):17–31, 2006. PMID: 16199119

    Campolongo, P.; Roozendaal, B.; Trezza, V.; et al. Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory. Proceedings of the National Academy of Sciences of the United States of America 106(12):4888–4893, 2009. PMID: 19255436

    Carver, C.S. You want to measure coping but your protocol’s too long: Consider the brief COPE. International Journal of Behavioral Medicine 4(1):92–100, 1997. PMID: 16250744

    Celerier, A.; Ognard, R.; Decorte, L.; and Beracochea, D. Deficits of spatial and non-spatial memory and of auditory fear conditioning following anterior thalamic lesions in mice: Comparison with chronic alcohol consumption. European Journal of Neuroscience 12:2575–2584, 2000. PMID: 10947832

    Centers for Disease Control and Prevention, National Center for Health Statistics. Health, United States, 2003 with Chartbook on Trends in the Health of Americans. Washington, DC: Department of Health and Human Services, 2003 [DHHS PHS No. 2003–1232].

    Charney, D.S. Psychobiological mechanisms of resilience and vulnerability: Implications for successful adaptation to extreme stress. American Journal of Psychiatry 161(2):195–216, 2004. PMID: 14754765

    Charuvastra, A., and Cloitre, M. Social bonds and posttraumatic stress disorder. Annual Review of Psychology 59:301–328, 2008. PMID: 17883334

    Cheer, J.F.; Wassum, K.M.; Sombers, L.A.; et al. Phasic dopamine release evoked by abused substances requires cannabinoid receptor activation. Journal of Neuroscience 27(4):791–795, 2007. PMID: 17251418

    Cicchetti, D., and Blender, J.A. A multiple-levels-of-analysis perspective on resilience: Implications for the developing brain, neural plasticity, and preventive interventions. Annals of the New York Academy of Sciences 1094:248–258, 2006. PMID: 17347356

    Clark, M.S., and Neumaier, J.F. The 5-HT1B receptor: Behavioral implications. Psychopharmacology Bulletin 35(4):170–185, 2001. PMID: 12397864

    Colombo, G.; Serra, S.; Brunetti, G.; et al. Stimulation of voluntary ethanol intake by cannabinoid receptor agonists in ethanol-preferring sP rats. Psychopharmacology (Berlin) 159(2):181–187, 2002. PMID: 11862347

    Cooper, M.L.; Russell, M.; Skinner, J.B.; et al. Stress and alcohol use: Moderating effects of gender, coping, and alcohol expectancies. Journal of Abnormal Psychology 101(1):139–152, 1992. PMID: 1537960

    Dai, X.; Thavundayil, J.; Santella, S.; and Gianoulakis, C. Response of the HPA-axis to alcohol and stress as a function of alcohol dependence and family history of alcoholism. Psychoneuroendocrinology 32(3):293–305, 2007. PMID: 17349749

    Dallman, M.F.; Pecoraro, N.C.; and la Fleur, S.E. Chronic stress and comfort foods: Self-medication and abdominal obesity. Brain, Behavior, and Immunity 19(4):275– 280, 2005. PMID: 15944067

    de Kloet, E.R.; Derijk, R.H.; and Meijer, O.C. Therapy Insight: Is there an imbalanced response of mineralocorticoid and glucocorticoid receptors in depression? Nature Clinical Practice Endocrinology & Metabolism 3(2):168–179, 2007. PMID: 17237843

    de Kloet, E.R.; Joels, M.; and Holsboer, F. Stress and the brain: From adaptation to disease. Nature Reviews. Neuroscience 6(6):463–475, 2005. PMID: 15891777

    Delgado, M.R.; Olsson, A.; and Phelps, E.A. Extending animal models of fear conditioning to humans. Biological Psychology 73(1):39–48, 2006. PMID: 16472906

    Devane, W.A.; Hanus, L.; Breuer, A.; et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258(5090):1946–1949, 1992. PMID: 1470919

    Di Marzo, V.; Fontana, A.; Cadas, H.; et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372(6507):686–691, 1994. PMID: 7990962

    Ding, Y.S.; Lin, K.S.; Logan, J.; et al. Comparative evaluation of positron emission tomography radiotracers for imaging the norepinephrine transporter: (S,S) and (R,R) enantiomers of reboxetine analogs ([11C]methylreboxetine, 3-Cl-[11C]methylreboxetine and [18F]fluororeboxetine), (R)-[11C]nisoxetine, [11C]oxaprotiline and [11C]lortalamine. Journal of Neurochemistry 94(2):337–351, 2005. PMID: 15998285

    Dom, G.; De Wilde, B.; Hulstijn, W.; et al. Decision-making deficits in alcohol-dependent patients with and without comorbid personality disorder. Alcoholism: Clinical and Experimental Research 30(10):1670–1677, 2006. PMID: 17010134

    Drabant, E.M.; Hariri, A.R.; Meyer-Lindenberg, A.; et al. Catechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation. Archives of General Psychiatry 63(12):1396– 1406, 2006. PMID: 17146014

    Drabant, E.M.; McRae, K.; Manuck, S.B.; et al. Individual differences in typical reappraisal use predict amygdala and prefrontal responses. Biological Psychiatry 65(5):367–373, 2009. PMID: 18930182

    Enoch, M.A. The role of early life stress as a predictor for alcohol and drug dependence. Psychopharmacology 214(1):17–31, 2011. PMID: 20596857

    Feder, A.; Nestler, E.J.; and Charney, D.S. Psychobiology and molecular genetics of resilience. Nature Reviews. Neuroscience 10(6):446–457, 2009. PMID: 19455174

    Femenia, T.; Garcia-Gutierrez, M.S.; and Manzanares, J. CB1 receptor blockade decreases ethanol intake and associated neurochemical changes in fawn-hooded rats. Alcoholism: Clinical and Experimental Research 34(1):131–141, 2010. PMID: 19860799

    Folkman, S., and Moskowitz, J.T. Coping: Pitfalls and promise. Annual Review of Psychology 55:745–774, 2004. PMID: 14744233

    Fredrickson, B.L. The role of positive emotions in positive psychology: The broaden-and-build theory of positive emotions. American Psychologist 56(3):218–226, 2001. PMID: 11315248

    Gallate, J.E.; Saharov, T.; Mallet, P.E.; and McGregor, I.S. Increased motivation for beer in rats following administration of a cannabinoid CB1 receptor agonist. European Journal of Pharmacology 370(3):233–240, 1999. PMID: 10334497

    Gianoulakis, C.; Dai, X.; Thavundayil, J.; and Brown, T. Levels and circadian rhythmicity of plasma ACTH, cortisol, and beta-endorphin as a function of family history of alcoholism. Psychopharmacology (Berlin) 181(3):437–444, 2005. PMID: 16133133

    Hakamata, Y.; Lissek, S.; Bar-Haim, Y.; et al. Attention bias modification treatment: A meta-analysis toward the establishment of novel treatment for anxiety. Biological Psychiatry 68(11):982–990, 2010. PMID: 20887977

    Hariri, A.R.; Drabant, E.M.; Munoz, K.E.; et al. A susceptibility gene for affective disorders and the response of the human amygdala. Archives of General Psychiatry 62(2):146–152, 2005. PMID: 15699291

    Heim, C., and Nemeroff, C.B. The role of childhood trauma in the neurobiology of mood and anxiety disorders: Preclinical and clinical studies. Biological Psychiatry 49(12):1023–1039, 2001. PMID: 11430844

    Herkenham, M.; Groen, B.G.; Lynn, A.B.; et al. Neuronal localization of cannabinoid receptors and second messengers in mutant mouse cerebellum. Brain Research 552(2):301–310, 1991. PMID: 1913192

    Herkenham, M.; Lynn, A.B.; Johnson, M.R.; et al. Characterization and localization of cannabinoid receptors in rat brain: A quantitative in vitro autoradiographic study. Journal of Neuroscience 11(2):563–583, 1991. PMID: 1992016

    Hill, M.N.; Hillard, C.J.; Bambico, F.R.; et al. The therapeutic potential of the endocannabinoid system for the development of a novel class of antidepressants. Trends in Pharmacological Sciences 30(9):484–493, 2009. PMID: 19732971

    Hill, M.N., and McEwen, B.S. Endocannabinoids: The silent partner of glucocorticoids in the synapse. Proceedings of the National Academy of Sciences of the United States of America 106(12):4579–4580, 2009. PMID: 19293387

    Hoebel, B.G.; Avena, N.M.; and Rada, P. Accumbens dopamine-acetylcholine balance in approach and avoidance. Current Opinion in Pharmacology 7(6):617–627, 2007. PMID: 18023617

    Hu, J.; Henry, S.; Gallezot, J.D.; et al. Serotonin 1B receptor imaging in alcohol dependence. Biological Psychiatry 67(9):800–803, 2010. PMID: 20172504

    Hungund, B.L.; Szakall, I.; Adam, A.; et al. Cannabinoid CB1 receptor knockout mice exhibit markedly reduced voluntary alcohol consumption and lack alcohol-induced dopamine release in the nucleus accumbens. Journal of Neurochemistry 84(4):698–704, 2003. PMID: 12562514

    Hyman, S.E.; Malenka, R.C.; and Nestler, E.J. Neural mechanisms of addiction: The role of reward-related learning and memory. Annual Review of Neuroscience 29:565–598, 2006. PMID: 16776597

    Johnstone, T.; van Reekum, C.M.; Urry, H.L.; et al. Failure to regulate: Counterproductive recruitment of top-down prefrontal-subcortical circuitry in major depression. Journal of Neuroscience 27(33):8877–8884, 2007. PMID: 17699669

    Kalivas, P.W., and Volkow, N.D. The neural basis of addiction: A pathology of motivation and choice. American Journal of Psychiatry 162(8):1403–1413, 2005. PMID: 16055761

    Kirby, L.B.; Zeeb, F.D.; and Winstanley, C.A. Contributions of serotonin in addiction vulnerability. Neuropharmacology 61(3):421–432, 2011. PMID: 21466815

    Kober, H.; Mende-Siedlecki, P.; Kross, E.F.; et al. Prefrontal-striatal pathway underlies cognitive regulation of craving. Proceedings of the National Academy of Sciences of the United States of America 107(33):14811–14816, 2010. PMID: 20679212

    Koehnke, M.D.; Schick, S.; Lutz, U.; et al. Severity of alcohol withdrawal symptoms and the T1128C polymorphism of the neuropeptide Y gene. Journal of Neural Transmission 109(11):1423–1429, 2002. PMID: 12454738

    Koob, G.F. Alcoholism: Allostasis and beyond. Alcoholism: Clinical and Experimental Research 27(2):232–243, 2003. PMID: 12605072

    Koob, G.F. Dynamics of neuronal circuits in addiction: Reward, antireward, and emotional memory. Pharmacopsychiatry 42 (Suppl. 1):S32–S41, 2009. PMID: 19434554

    Koob, G.F.; Ahmed, S.H.; Boutrel, B.; et al. Neurobiological mechanisms in the transition from drug use to drug dependence. Neuroscience and Biobehavioral Reviews 27(8):739–749, 2004. PMID: 15019424

    Koob, G.F., and Le Moal, M. Drug abuse: Hedonic homeostatic dysregulation. Science 278(5335):52–58, 1997. PMID: 9311926

    Koob, G.F., and Le Moal, M. Review: Neurobiological mechanisms for opponent motivational processes in addiction. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 363(1507):3113–3123, 2008. PMID: 18653439

    Krystal, J.H., and Neumeister, A. Noradrenergic and serotonergic mechanisms in the neurobiology of posttraumatic stress disorder and resilience. Brain Research 1293:13–23, 2009. PMID: 19332037

    Lazarus, R.S., and Fokman, S. Stress, Appraisal, and Coping. New York: Springer, 1984.

    Le, A.D.; Harding, S.; Juzytsch, W.; et al. Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Psychopharmacology (Berlin) 179(2):366–373, 2005. PMID: 15551068

    Lee, V.; Cohen, S.R.; Edgar, L.; et al. Clarifying “meaning” in the context of cancer research: A systematic literature review. Palliative & Supportive Care 2(3):291–303, 2004. PMID: 16594414

    Lindell, S.G.; Schwandt, M.L.; Sun, H.; et al. Functional NPY variation as a factor in stress resilience and alcohol consumption in rhesus macaques. Archives of General Psychiatry 67(4):423–431, 2010. PMID: 20368518

    Maccioni, P.; Pes, D.; Carai, M.A.; et al. Suppression by the cannabinoid CB1 receptor antagonist, rimonabant, of the reinforcing and motivational properties of a chocolate-flavoured beverage in rats. Behavioural Pharmacology 19(3):197–209, 2008. PMID: 18469537

    Mackie, K. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handbook of Experimental Pharmacology 168:299–325, 2005. PMID: 16596779

    MacQueen, G.M.; Campbell, S.; McEwen, B.S.; et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proceedings of the National Academy of Sciences of the United States of America 100(3):1387–1392, 2003. PMID: 12552118

    Malinen, H., and Hyytia, P. Ethanol self-administration is regulated by CB1 receptors in the nucleus accumbens and ventral tegmental area in alcohol-preferring AA rats. Alcoholism: Clinical and Experimental Research 32(11):1976–1983, 2008. PMID: 18782338

    Mangieri, R.A.; Hong, K.I.; Piomelli, D.; and Sinha, R. An endocannabinoid signal associated with desire for alcohol is suppressed in recently abstinent alcoholics. Psychopharmacology (Berlin) 205(1):63–72, 2009. PMID: 19343330

    Marinelli, P.W.; Bai, L.; Quirion, R.; and Gianoulakis, C. A microdialysis profile of Met-enkephalin release in the rat nucleus accumbens following alcohol administration. Alcoholism: Clinical and Experimental Research 29(10):1821–1828, 2005. PMID: 16269911

    Marinelli, P.W.; Funk, D.; Juzytsch, W.; et al. The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacology (Berlin) 195(3):345–355, 2007. PMID: 17705061

    Marlatt, G.A. Should abstinence be the goal for alcohol treatment? Negative viewpoint. American Journal on Addictions 10(4):291–293, 2001. PMID: 11783743

    Masten, A.S. Ordinary magic: Resilience processes in development. American Psychologist 56(3):227–238, 2001. PMID: 11315249

    Masten, A.S., and Coatsworth, J.D. The development of competence in favorable and unfavorable environments: Lessons from research on successful children. American Psychologist 53(2):205–220, 1998. PMID: 9491748

    Matsuda, L.A.; Bonner, T.I.; and Lolait, S.J. Localization of cannabinoid receptor mRNA in rat brain. Journal of Comparative Neurology 327(4):535–550, 1993. PMID: 8440779

    McCool, B.A.; Christian, D.T.; Diaz, M.R.; and Lack, A.K. Glutamate plasticity in the drunken amygdala: The making of an anxious synapse. International Review of Neurobiology 91:205–233, 2010. PMID: 20813244

    McEwen, B.S. Allostasis and allostatic load: Implications for neuropsychopharmacology. Neuropsychopharmacology 22(2):108–124, 2000. PMID: 10649824

    McEwen, B.S. Mood disorders and allostatic load. Biological Psychiatry 54(3):200–207, 2003. PMID: 12893096

    Mechoulam, R.; Ben-Shabat, S.; Hanus, L.; et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochemical Pharmacology 50(1):83–90, 1995. PMID: 7605349

    Milad, M.R.; Quinn, B.T.; Pitman, R.K.; et al. Thickness of ventromedial prefrontal cortex in humans is correlated with extinction memory. Proceedings of the National Academy of Sciences of the United States of America 102(30):10706–10711, 2005. PMID: 16024728

    Miller, W.R.; Westerberg, V.S.; Harris, R.J.; and Tonigan, J.S. What predicts relapse? Prospective testing of antecedent models. Addiction 91(Suppl.):S155–S172, 1996. PMID: 8997790

    Miner, L.H.; Jedema, H.P.; Moore, F.W.; et al. Chronic stress increases the plasmalemmal distribution of the norepinephrine transporter and the coexpression of tyrosine hydroxylase in norepinephrine axons in the prefrontal cortex. Journal of Neuroscience 26(5):1571–1578, 2006. PMID: 16452680

    Morgan, C.A., 3rd; Wang, S.; Southwick, S.M.; et al. Plasma neuropeptide-Y concentrations in humans exposed to military survival training. Biological Psychiatry 47(10):902–909, 2000. PMID: 10807963

    Mottagui-Tabar, S.; Prince, J.A.; Wahlestedt, C.; et al. A novel single nucleotide polymorphism of the neuropeptide Y (NPY) gene associated with alcohol dependence. Alcoholism: Clinical and Experimental Research 29(5):702–707, 2005. PMID: 15897713

    Naassila, M.; Pierrefiche, O.; Ledent, C.; and Daoust, M. Decreased alcohol self-administration and increased alcohol sensitivity and withdrawal in CB1 receptor knockout mice. Neuropharmacology 46(2):243–253, 2004. PMID: 14680762

    Neumeister, A.; Charney, D.S.; Belfer, I.; et al. Sympathoneural and adrenomedullary functional effects of alpha2C-adrenoreceptor gene polymorphism in healthy humans. Pharmacogenetics and Genomics 15(3):143–149, 2005. PMID: 15861038

    O’Brien, C.P.; Childress, A.R.; Ehrman, R.; and Robbins, S.J. Conditioning factors in drug abuse: Can they explain compulsion? Journal of Psychopharmacology 12(1):15–22, 1998. PMID: 9584964

    O’Donnell, T.; Hegadoren, K.M.; and Coupland, N.C. Noradrenergic mechanisms in the pathophysiology of post-traumatic stress disorder. Neuropsychobiology 50(4):273–283, 2004. PMID: 15539856

    Ong, A.D.; Bergeman, C.S.; Bisconti, T.L.; and Wallace, K.A. Psychological resilience, positive emotions, and successful adaptation to stress in later life. Journal of Personality and Social Psychology 91(4):730–749, 2006. PMID: 17014296

    Pargament, K.I.; Smith, B.W.; Koenig, H.G.; and Perez, L. Patterns of positive and negative religious coping with major life stressors. Journal for the Scientific Study of Religion 37:710–724, 1998.

    Pezawas, L.; Meyer-Lindenberg, A.; Drabant, E.M.; et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: A genetic susceptibility mechanism for depression. Nature Neuroscience 8(6):828– 834, 2005. PMID: 15880108

    Poncelet, M.; Maruani, J.; Calassi, R.; and Soubrie, P. Overeating, alcohol and sucrose consumption decrease in CB1 receptor deleted mice. Neuroscience Letters 343(3):216–218, 2003. PMID: 12770700

    Rauch, S.L.; Shin, L.M.; and Phelps, E.A. Neurocircuitry models of posttraumatic stress disorder and extinction: Human neuroimaging research—past, present, and future. Biological Psychiatry 60(4):376–382, 2006. PMID: 16919525

    Richardson, K.; Baillie, A.; Reid, S.; et al. Do acamprosate or naltrexone have an effect on daily drinking by reducing craving for alcohol? Addiction 103(6):953–959, 2008. PMID: 18482418

    Robles, T.F., and Kiecolt-Glaser, J.K. The physiology of marriage: Pathways to health. Physiology & Behavior 79(3):409–416, 2003. PMID: 12954435

    Roffman, J.L.; Marci, C.D.; Glick, D.M.; et al. Neuroimaging and the functional neuroanatomy of psychotherapy. Psychological Medicine 35(10):1385– 1398. PMID: 16164763

    Ross, S., and Peselow, E. The neurobiology of addictive disorders. Clinical Neuropharmacology 32(5):269–276, 2009. PMID: 19834992

    Rutter, M. Resilience in the face of adversity: Protective factors and resistance to psychiatric disorder. British Journal of Psychiatry 147:598–611, 1985. PMID: 3830321

    Sallinen, J.; Haapalinna, A.; MacDonald, E.; et al. Genetic alteration of the alpha2-adrenoceptor subtype c in mice affects the development of behavioral despair and stress-induced increases in plasma corticosterone levels. Molecular Psychiatry 4(5):443–452, 1999. PMID: 10523817

    Sari, Y. Serotonin1B receptors: From protein to physiological function and behavior. Neuroscience and Biobehavioral Reviews 28(6):565–582, 2004. PMID: 15527863

    Schmid, B.; Blomeyer, D.; Treutlein, J.; et al. Interacting effects of CRHR1 gene and stressful life events on drinking initiation and progression among 19-year-olds. International Journal of Neuropsychopharmacology 13(6):703–714, 2010. PMID: 19607758

    Schuckit, M.A., and Smith, T.L. An 8-year follow-up of 450 sons of alcoholic and control subjects. Archives of General Psychiatry 53(3):202–210, 1996. PMID: 8611056

    Seligman, M.E., and Csikszentmihalyi, M. Positive psychology: An introduction. American Psychologist 55(1):5–14, 2000. PMID: 11392865

    Selye, H. The Stress of Life. New York: McGraw-Hill, 1976.

    Shapiro, S.L.; Schwartz, G.E.; and Bonner, G. Effects of mindfulness-based stress reduction on medical and premedical students. Journal of Behavioral Medicine 21(6):581–599, 1998. PMID: 9891256

    Sinha, R. How does stress increase risk of drug abuse and relapse? Psychopharmacology (Berlin) 158(4):343–359, 2001. PMID: 11797055

    Sinha, R.; Fox, H.C.; Hong, K.I.; et al. Effects of adrenal sensitivity, stress- and cue-induced craving, and anxiety on subsequent alcohol relapse and treatment outcomes. Archives of General Psychiatry 68(9):942–952, 2011. PMID: 21536969

    Small, K.M.; Forbes, S.L.; Rahman, F.F.; et al. A four amino acid deletion polymorphism in the third intracellular loop of the human alpha 2C-adrenergic receptor confers impaired coupling to multiple effectors. Journal of Biological Chemistry 275(30):23059–23064, 2000. PMID: 10801795

    Southwick, S.M.; Vythilingam, M.; and Charney, D.S. The psychobiology of depression and resilience to stress: Implications for prevention and treatment. Annual Review of Clinical Psychology 1:255–291, 2005. PMID: 17716089

    Stella, N.; Schweitzer, P.; and Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 388(6644):773–778, 1997. PMID: 9285589

    Stephens, D.N.; Ripley, T.L.; Borlikova, G.; et al. Repeated ethanol exposure and withdrawal impairs human fear conditioning and depresses long-term potentiation in rat amygdala and hippocampus. Biological Psychiatry 58(5):392–400, 2005. PMID: 16018978

    Sterling, P., and Eyer, J. Allostasis: A New Paradigm to Explain Arousal Pathology. New York: John Wiley & Sons, 1988.

    Sugiura, T.; Kondo, S.; Sukagawa, A.; et al. 2-Arachi­donoylglycerol: A possible endogenous cannabinoid receptor ligand in brain. Biochemical and Biophysical Research Communications 215(1):89–97, 1995. PMID: 7575630

    Sullivan, E.V., and Pfefferbaum, A. Neurocircuitry in alcoholism: A substrate of disruption and repair. Psychopharmacology (Berlin) 180(4):583–594, 2005. PMID: 15834536

    Teasdale, J.D.; Segal, Z.V.; Williams, J.M.; et al. Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy. Journal of Consulting and Clinical Psychology 68(4):615–623, 2000. PMID: 10965637

    Thanos, P.K.; Michaelides, M.; Umegaki, H.; and Volkow, N.D. D2R DNA transfer into the nucleus accumbens attenuates cocaine self-administration in rats. Synapse 62(7):481–486, 2008. PMID: 18418874

    Thiele, T.E.; Marsh, D.J.; Ste. Marie, L.; et al. Ethanol consumption and resistance are inversely related to neuropeptide Y levels. Nature 396(6709):366–369, 1998. PMID: 9845072

    Thorsell, A. Neuropeptide Y (NPY) in alcohol intake and dependence. Peptides 28(2): 480–483, 2007. PMID: 17239487

    Tugade, M.M., and Fredrickson, B.L. Resilient individuals use positive emotions to bounce back from negative emotional experiences. Journal of Personality and Social Psychology 86(2):320–333, 2004. PMID: 14769087

    Van Sickle, M.D.; Duncan, M.; Kingsley, P.J.; et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310 (5746): 329–332, 2005. PMID: 16224028

    Veenstra, M.Y.; Lemmens, P.H.; Friesema, I.H.; et al. Coping style mediates impact of stress on alcohol use: A prospective population-based study. Addiction 102(12):1890–1898, 2007. PMID: 18031425

    Vinod, K.Y., and Hungund, B.L. Cannabinoid-1 receptor: A novel target for the treatment of neuropsychiatric disorders. Expert Opinion on Therapeutic Targets 10(2):203– 210, 2006. PMID: 16548770

    Vinod, K.Y.; Sanguino, E.; Yalamanchili, R.; et al. Manipulation of fatty acid amide hydrolase functional activity alters sensitivity and dependence to ethanol. Journal of Neurochemistry 104(1):233–243, 2008bPMID: 17944864

    Vinod, K.Y.; Yalamanchili, R.; Thanos, P.K.; et al. Genetic and pharmacological manipulations of the CB(1) receptor alter ethanol preference and dependence in ethanol preferring and nonpreferring mice. Synapse 62(8):574–581, 2008aPMID: 18509854

    Vinod, K.Y.; Yalamanchili, R.; Xie, S.; et al. Effect of chronic ethanol exposure and its withdrawal on the endocannabinoid system. Neurochemistry International 49(6):619–625, 2006. PMID: 16822589

    Vinod, K.Y.; Kassir, S.A.; Hungund, B.L.; et al. Selective alterations of the CB1 receptors and the fatty acid amide hydrolase in the ventral striatum of alcoholics and suicides. Journal of Psychiatric Research 44(9):591–597, 2010. PMID: 20015515

    Volkow, N.D.; Fowler, J.S.; and Wang, G.J. Role of dopamine in drug reinforcement and addiction in humans: Results from imaging studies. Behavioural Pharmacology 13(5–6):355–366, 2002. PMID: 12394411

    Volkow, N.D.; Wang, G.J.; Begleiter, H.; et al. High levels of dopamine D2 receptors in unaffected members of alcoholic families: Possible protective factors. Archives of General Psychiatry 63(9):999–1008, 2006. PMID: 16953002

    Volkow, N.D.; Wang, G.J.; Fowler, J.S.; et al. Addiction: Decreased reward sensitivity and increased expectation sensitivity conspire to overwhelm the brain’s control circuit. BioEssays 32(9):748–755, 2010. PMID: 20730946

    Volkow, P.; Tellez, O.; Allende, S.; and Vazquez, C. Drug abuse through a long-indwelling catheter cared for by an intravenous team. American Journal of Infection Control 27(5):459, 1999. PMID: 10511497

    Vythilingam, M.; Nelson, E.E.; Scaramozza, M.; et al. Reward circuitry in resilience to severe trauma: An fMRI investigation of resilient special forces soldiers. Psychiatry Research 172(1):75–77, 2009. PMID: 19243926

    Wager, T.D.; Davidson, M.L.; Hughes, B.L.; et al. Prefrontal-subcortical pathways mediating successful emotion regulation. Neuron 59(6):1037–1050, 2008. PMID: 18817740

    Wetherill, L.; Schuckit, M.A.; Hesselbrock, V.; et al. Neuropeptide Y receptor genes are associated with alcohol dependence, alcohol withdrawal phenotypes, and cocaine dependence. Alcoholism: Clinical and Experimental Research 32(12):2031–2040, 2008. PMID: 18828811

    Wills, T.A.; Sandy, J.M.; Yaeger, A.M.; et al. Coping dimensions, life stress, and adolescent substance use: A latent growth analysis. Journal of Abnormal Psychology 110(2):309–323. PMID: 11358025

    Yacubian, J.; Sommer, T.; Schroeder, K.; et al. Gene–gene interaction associated with neural reward sensitivity. Proceedings of the National Academy of Sciences of the United States of America 104(19):8125–8130, 2007. PMID: 17483451

    Yehuda, R., and LeDoux, J. Response variation following trauma: A translational neuroscience approach to understanding PTSD. Neuron 56(1):19–32, 2007. PMID: 17920012

    Zhang, H.; Sakharkar, A.J.; Shi, G.; et al. Neuropeptide Y signaling in the central nucleus of amygdala regulates alcohol-drinking and anxiety-like behaviors of alcohol-preferring rats. Alcoholism: Clinical and Experimental Research 34(3):451–461, 2010. PMID: 20028368