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Functional CRH variation increases stress-induced alcohol consumption in primates.

ABSTRACT: Corticotropin-releasing factor (CRF), encoded by the CRH gene, is a key integrator of stress responses, and, as such, CRH gene variation may contribute to individual differences in susceptibility to stress-related pathology. In rhesus macaques, a single nucleotide polymorphism (SNP) is found within the CRH promoter (-248C--> T). Here, we assessed whether this variant influenced stress responding and, because increased CRF system activity drives alcohol drinking in rodents, we examined whether it predicted voluntary alcohol consumption as a function of prior stress exposure. Using a hypothalamic nuclear extract, we showed that the -248 T allele resulted in increased DNA protein interactions relative to the C allele. In vitro, the T allele resulted in CRH promoter activity that was higher following both stimulation with forskolin and treatment with dexamethasone. Endocrine and behavioral responses to social separation stress (release of ACTH and cortisol, and suppression of environmental exploration, respectively) were higher among carriers of the T allele, particularly among those exposed to early adversity in the form of peer rearing. We also found that T allele carriers with a history of early life adversity consumed more alcohol in a limited-access paradigm. Our data suggest that CRH promoter variation that confers increased stress reactivity increases the risk for alcohol use disorders in stress-exposed individuals.

SUBMITTER: Barr CS

PROVIDER: S-EPMC2732884 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Functional CRH variation increases stress-induced alcohol consumption in primates.

Barr Christina S CS Dvoskin Rachel L RL Gupte Manisha M Sommer Wolfgang W Sun Hui H Schwandt Melanie L ML Lindell Stephen G SG Kasckow John W JW Suomi Stephen J SJ Goldman David D Higley J Dee JD Heilig Markus M

Proceedings of the National Academy of Sciences of the United States of America 20090817 34

Corticotropin-releasing factor (CRF), encoded by the CRH gene, is a key integrator of stress responses, and, as such, CRH gene variation may contribute to individual differences in susceptibility to stress-related pathology. In rhesus macaques, a single nucleotide polymorphism (SNP) is found within the CRH promoter (-248C--> T). Here, we assessed whether this variant influenced stress responding and, because increased CRF system activity drives alcohol drinking in rodents, we examined whether it ...[more]

PMID: 19706546

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Project description:CONTEXT:Neuropeptide Y (NPY) counters stress and is involved in neuroadaptations that drive escalated alcohol drinking in rodents. In humans, low NPY expression predicts amygdala response and emotional reactivity. Genetic variation that affects the NPY system could moderate stress resilience and susceptibility to alcohol dependence. OBJECTIVE:To determine whether functional NPY variation influences behavioral adaptation to stress and alcohol consumption in a nonhuman primate model of early adversity (peer rearing). DESIGN:We sequenced the rhesus macaque NPY locus (rhNPY) and performed in silico analysis to identify functional variants. We performed gel shift assays using nuclear extract from testes, brain, and hypothalamus. Levels of NPY in cerebrospinal fluid were measured by radioimmunoassay, and messenger RNA levels were assessed in the amygdala using real-time polymerase chain reaction. Animals were exposed to repeated social separation stress and tested for individual differences in alcohol consumption. Animals were genotyped for -1002 T > G, and the data were analyzed using analysis of variance. SETTING:National Institutes of Health Animal Center. Subjects Ninety-six rhesus macaques. Main Outcome Measure Behavior arousal during social separation stress and ethanol consumption. RESULTS:The G allele altered binding of regulatory proteins in all nuclear extracts tested, and -1002 T > G resulted in lower levels of NPY expression in the amygdala. Macaques exposed to adversity had lower cerebrospinal fluid NPY levels and exhibited higher levels of arousal during stress, but only as a function of the G allele. We also found that stress-exposed G allele carriers consumed more alcohol and exhibited an escalation in intake over cycles of alcohol availability and deprivation. CONCLUSIONS:Our results suggest a role for NPY promoter variation in the susceptibility to alcohol use disorders and point to NPY as a candidate for examining gene x environment interactions in humans.

Project description:RationaleChronic alcohol misuse can escalate into alcohol use disorder (AUD). The causal mechanisms through which recreational social drinking develops into compulsive uncontrolled alcohol misuse are multifaceted. For example, stress is an important risk factor that influences alcohol craving in both healthy and addicted individuals. In addition, those that are high in impulsivity/risk taking drink more and are at greater risk of developing addiction. At present, however, it is not possible accurately to predict those at risk of escalation in alcohol use, or of developing AUD.ObjectivesThe aim of this study was to investigate how underlying physiological and personality traits affect stress-induced craving for, and consumption of, alcohol, in a sample of social drinkers. The primary hypothesis was that impulsivity/risk-taking would modulate stress-induced alcohol craving and consumption.MethodsThirty-nine participants (22 male and 17 female; mean age = 23.92 years [SD = 4.90]) were randomly allocated to 'stress' and 'no-stress' groups; in the stress group, participants took part in the Trier Social Stress Test (TSST). Participants completed several questionnaires and computer tasks in order to assess prior alcohol use, impulsivity/risk-taking, stress-reactivity, craving and physiological biomarkers of stress. Finally, participants completed a voluntary drinking task, in which increasing numbers of presses on a computer keyboard were reinforced with 5-ml shots of 37% ABV vodka (plus mixer).ResultsParticipants exposed to the TSST showed an increase in craving following the stressor. Several factors predicted voluntary drinking, including risky decision making, slow HR recovery from stress, poor vagal tone during recovery from stress and greater stress reactivity. Surprisingly, we found no correlation between craving and consumption.ConclusionsOur data suggest that variation in physiological stress parameters and poor decision-making abilities increase risk of stress-induced alcohol consumption. This may provide a useful translational framework through which we can further study early predictive markers for the shift between controlled recreational drinking to uncontrolled alcohol misuse, including AUD.

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Functional CRH variation increases stress-induced alcohol consumption in primates.

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Functional CRH variation increases stress-induced alcohol consumption in primates.

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