Stress Effects on Alcohol Consumption: Age of onset and genes in heavy drinkers

描述(由申请人提供)：INIA的研究人员和其他人假设，压力和酒精暴露会触发特效过程，损害边缘和下丘脑的应激通路，并为饮酒增加铺平道路。这一理论得到了美国人群流行病学研究的支持，即生活应激源的数量与饮酒量呈正相关，并且这些影响在较早开始饮酒的人中最强。最近的研究表明，5-羟色胺转运体启动子多态性和压力在预测总酒精摄入量、饮酒开始年龄和饮酒持续时间方面具有重要的调节作用。促肾上腺皮质激素释放激素(CRH)受体1的遗传变异也与应激诱导的动物和人类青少年大量饮酒有关；CRH的作用一直是INIA的一个主要焦点。我们假设，在人类实验室中，社会应激程序会增加酒精刺激的反应和酒精消耗量，这种关系将被饮酒开始年龄和正在研究的基因所改变。为了验证我们的假设，没有寻求治疗的、有或没有酒精使用障碍的重度饮酒者将被允许进入酒精戒毒的临床研究单位。禁欲开始四天后，受试者将按随机顺序接受特里尔社会压力测试(TSST)或在时间匹配的中性条件下进行；皮质醇将在这些过程中进行测量。在TSST或中性条件下，将立即使用可操作的自我给药模式提供酒精供应，在这种模式下，响应需求随着每获得一杯酒精饮料而逐渐增加；获得的酒精在会议结束时交付。我们还将使用酒精敏感性程序来研究受试者，该程序建立了酒精对主观、生理和行为测量的剂量-效应函数。研究结果将对建立基因和环境对酗酒者压力和酒精关系的潜在影响机制具有科学和临床意义。

DESCRIPTION (provided by applicant): INIA researchers and others have posited that stress and alcohol exposure trigger allostatic processes which injure limbic and hypothalamic stress pathways and set the stage for increased drinking. This theory is supported by epidemiological findings in the US population that number of life stressors is positively correlated with amount of alcohol consumption and that these effects are strongest in persons with an early onset of alcohol use. Recent studies suggest important modifying effects of the serotonin transporter promoter polymorphism and stress in predicting total alcohol intake, age of onset of drinking, and duration of drinking. Genetic variation in the corticotropin-releasing hormone (CRH) receptor 1 also has been associated with stress-induced heavy alcohol consumption in animals and human adolescents; the role of CRH has been a major focus of INIA. We hypothesize that, in the human laboratory, a social stress procedure will increase alcohol motivated responding and alcohol consumption, and that this relationship will be modified by age of drinking onset and the genes under investigation. To test our hypotheses, non-treatment seeking, heavy alcohol drinkers with and without an alcohol use disorder will be admitted to the clinical research unit for alcohol detoxification. Four days after the start of abstinence, subjects will undergo in random order, the Trier Social Stress Test (TSST) or a time-matched neutral condition; Cortisol will be measured during these procedures. Immediately after the TSST or neutral condition, access to alcohol will be provided using an operant self-administration paradigm in which the response demands progressively increase with each alcohol drink that is earned; earned alcohol is delivered at the conclusion of the session. We also will study subjects using an alcohol sensitivity procedure that establishes a dose-effect function for alcohol on subjective, physiological and behavioral measures within a single session. Study findings will have scientific and clinical importance in establishing potential mechanisms for genetic and environmental influences on the relationship between stress and alcohol in heavy drinkers.