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.

Preclinical research has shown that stress, in addition to drug itself, plays a key role in perpetuating drug abuse and relapse. However, the mechanisms underlying this association in humans remain unclear. A greater understanding of how stress may perpetuate drug abuse will likely have a significant impact on both prevention and treatment development in the field of addiction.

Background Psychological stress and physical activity (PA) are believed to be reciprocally related; however, most research examining the relationship between these constructs is devoted to the study of exercise and/or PA as an instrument to mitigate distress. Objective The aim of this paper was to review the literature investigating the influence of stress on indicators of PA and exercise. Methods A systematic search of Web of Science, Pub-Med, and SPORTDiscus was employed to find all relevant studies focusing on human participants. Search terms included “stress”, “exercise”, and “physical activity”. A rating scale (0–9) modified for this study was utilized to assess the quality of all studies with multiple time points. Results The literature search found 168 studies that examined the influence of stress on PA. Studies varied widely in their theoretical orientation and included perceived stress, distress, life events, job strain, role strain, and work–family conflict but not lifetime cumulative adversity. To more clearly address the question, prospective studies (n = 55) were considered for further review, the majority of which indicated that psychological stress predicts less PA (behavioral inhibition) and/or exercise or more sedentary behavior (76.4 %). Both objective (i.e., life events) and subjective (i.e., distress) measures of stress related to reduced PA. Prospective studies investigating the effects of objective markers of stress nearly all agreed (six of seven studies) that stress has a negative effect on PA. This was true for research examining (a) PA at periods of objectively varying levels of stress (i.e., final examinations vs. a control time point) and (b) chronically stressed populations (e.g., caregivers, parents of children with a cancer diagnosis) that were less likely to be active than controls over time. Studies examining older adults (>50 years), cohorts with both men and women, and larger sample sizes (n > 100) were more likely to show an inverse association. 85.7 % of higher-quality prospective research (≥7 on a 9-point scale) showed the same trend. Interestingly, some prospective studies (18.2 %) report evidence that PA was positively impacted by stress (behavioral activation). This should not be surprising as some individuals utilize exercise to cope with stress. Several other factors may moderate stress and PA relationships, such as stages of change for exercise. Habitually active individuals exercise more in the face of stress, and those in beginning stages exercise less. Consequently, stress may have a differential impact on exercise adoption, maintenance, and relapse. Preliminary evidence suggests that combining stress management programming with exercise interventions may allay stress-related reductions in PA, though rigorous testing of these techniques has yet to be produced. Conclusions Overall, the majority of the literature finds that the experience of stress impairs efforts to be physically active. Future work should center on the development of a theory explaining the...

Chronic alcohol abuse is associated with changes in stress and reward pathways that could alter vulnerability to emotional stress and alcohol craving. This study examines whether chronic alcohol abuse is associated with altered stress and alcohol craving responses. Treatment-engaged, 28-day abstinent alcohol-dependent individuals (ADs; 6F/22M), and social drinkers (SDs; 10F/18M) were exposed to a brief guided imagery of a personalized stressful, alcohol-related and neutral-relaxing situation, one imagery condition per session, presented in random order across 3 days. Alcohol craving, anxiety and emotion ratings, behavioral distress responses, heart rate, blood pressure, and salivary cortisol measures were assessed. Alcohol patients showed significantly elevated basal heart rate and salivary cortisol levels. Stress and alcohol cue exposure each produced a significantly enhanced and persistent craving state in alcohol patients that was marked by increased anxiety, negative emotion, systolic blood pressure responses, and, in the case of alcohol cue, behavioral distress responses, as compared to SDs. Blunted stress-induced cortisol responses were observed in the AD compared to the SD group. These data are the first to document that stress and cue exposure induce a persistent negative emotion-related alcohol craving state in abstinent alcoholics accompanied by dysregulated HPA and physiological arousal responses. As laboratory models of stress and negative mood-induced alcohol craving are predictive of relapse outcomes, one implication of the current data is that treatments targeting decreases in stress and alcohol cue-induced craving and regulation of stress responses could be of benefit in improving alcohol relapse outcomes.

These results demonstrate that stress-related increases in cocaine craving and hypothalamic-pituitary-adrenal axis responses are each associated with specific cocaine relapse outcomes. The findings support the use of stress-induced drug craving and associated hypothalamic-pituitary-adrenal axis responses to evaluate cocaine relapse propensity. Furthermore, treatments that address stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses could be of benefit in improving relapse outcomes in cocaine dependence.

These results confirm the hypothesis that naltrexone reduces desire to drink and the amount of alcohol consumed in alcohol-dependent subjects. It is hypothesized that naltrexone may reduce drinking via suppressing craving for alcohol and that this effect may be related in part to naltrexone's ability to activate the hypothalamo-pituitary-adrenocortical axis.

Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic 1,2 and its release is induced by stress 3 . NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories [4][5][6] . Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in postmortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases.Reprints and permissions information is available at www.nature.com/reprints. Correspondence and requests for materials should be addressed to D.G. (E-mail: davidgoldman@mail.nih.gov). * These authors contributed equally to this work. † Present address: Innovation Centre China, AstraZeneca Global R&D, Shanghai 201203, China. Supplementary Fig. 1b). Five haplotypes (H1-H5) account for 93.8% of chromosomes in this block (Fig. 1a).We observed haplotype-driven NPY mRNA expression in postmortem brain (US Caucasians, Miami sample) by detecting the differential expression of alleles at single nucleotide polymorphism (SNP) rs5574 C/T, selected because of its high frequency and location in the transcript. Of these 28 samples, chosen because all were heterozygous for rs5574, 16 (57%) showed differential allele expression at an allele ratio of more than 1.2, in either direction. H1 and H4 were low-expression haplotypes, H2 was high, H3 was intermediate and H5 was unclassified because only two H1/H5 heterozygous brains were available (Fig. 1b). This expression-based functional classification is consistent with a cladistically based clustering of haplotypes, indicating that expression variation is linked to gene ancestry (Fig. 1a). The effects on expression of the more common H1, H2 and H3 haplotypes were verified in 47 lymphoblastoid cell lines derived from healthy Finnish men ( Fig. 1c) representing the six common diplotypes (72% of all diplotypes). On the basis of lymphoblast NPY mRNA levels, the expression value for each haplotype was calculated by regression analysis. Expression values for the six common diplotypes were well predicted under a co...

Stress is associated with obesity and the neurobiology of stress overlaps significantly with that of appetite and energy regulation. This review will discuss stress, allostasis, the neurobiology of stress and its overlap with neural regulation of appetite and energy homeostasis. Stress is a key risk factor in the development of addiction and in addiction relapse. High levels of stress changes eating patterns and augments consumption of highly palatable (HP) foods, which in turn, increases incentive salience of HP foods and allostatic load. The neurobiological mechanisms by which stress affects reward pathways to potentiate motivation and consumption of HP foods as well as addictive drugs is discussed. With enhanced incentive salience of HP foods and over-consumption of these foods, there are adaptations in stress and reward circuits that promote stress-related and HP food-related motivation as well as concomitant metabolic adaptations, including alterations in glucose metabolism, insulin sensitivity, and other hormones related to energy homeostatsis. These metabolic changes in turn may also affect dopaminergic activity to influence food motivation and intake of HP foods. An integrative heuristic model is proposed wherein repeated high levels of stress alter the biology of stress and appetite/energy regulation, with both components directly affecting neural mechanisms contributing to stress-induced and food cue-induced HP food motivation and engagement in overeating of such foods to enhance risk of weight gain and obesity. Future directions in research are identified to increase understanding of the mechanisms by which stress may increase risk of weight gain and obesity.