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

描述（由申请人提供）：INIA研究人员和其他人认为，压力和酒精暴露触发了非稳态过程，损伤了边缘系统和下丘脑压力通路，并为增加饮酒奠定了基础。这一理论得到了美国人群流行病学调查结果的支持，即生活压力源的数量与饮酒量呈正相关，并且这些影响在早期饮酒的人中最强。最近的研究表明，5-羟色胺转运蛋白启动子多态性和压力在预测总酒精摄入量，饮酒开始的年龄和饮酒时间方面具有重要的修饰作用。促肾上腺皮质激素释放激素（CRH）受体1的遗传变异也与动物和人类青少年中应激诱导的大量饮酒有关; CRH的作用一直是INIA的主要焦点。我们假设，在人类实验室中，社会压力程序将增加酒精动机的反应和酒精消费，这种关系将被修改的年龄饮酒发作和正在调查的基因。为了验证我们的假设，非寻求治疗，重度饮酒者与酒精使用障碍和没有将被接纳为酒精解毒的临床研究单位。开始禁欲后4天，受试者将以随机顺序接受特里尔社会压力测试（TSST）或时间匹配的中性条件;在这些程序期间将测量皮质醇。在TSST或中性条件后，将立即使用操作性自我给药模式提供酒精，其中响应需求随着每次获得的酒精饮料而逐渐增加;在会话结束时提供获得的酒精。我们还将使用酒精敏感性程序研究受试者，该程序在单次会议中建立了酒精对主观，生理和行为测量的剂量效应函数。研究结果将在建立遗传和环境影响重度饮酒者压力和酒精之间关系的潜在机制方面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.