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

压力对饮酒的影响：酗酒者的发病年龄和基因

• 批准号: 8425097
• 负责人: MARY E MCCAUL
• 金额: $ 29.16万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425097
• 关键词: Abstinence; Adolescent; Age; Age of Onset; Alcohol consumption; Alcohol dependence; Alcoholic beverage heavy drinker; Alcohols; Alleles; Animals; Applications Grants; Autonomic nervous system; Chronic stress; Clinical; Clinical Research; Consumption; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Dose; Drug Addiction; Drug Metabolic Detoxication; Epidemiology; Exposure to; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Glucocorticoids; Heart Rate; Heavy Drinking; Homeostasis; Hormones; Human; Hydrocortisone; Hypothalamic structure; Immune; Inflammatory; Investigation; Laboratories; Life; Mammals; Measures; Mediator of activation protein; Mental Depression; Minor; Neurosecretory Systems; Nucleic Acid Regulatory Sequences; Organism; Pathway interactions; Peptides; Persons; Physiological; Population; Prevention strategy; Procedures; Process; Research Personnel; Role; Schedule; Self Administration; Series; Staging; Stimulus; Stress; Study Subject; Testing; Time; Trier Social Stress Test; alcohol abstinence; alcohol availability; alcohol craving; alcohol exposure; alcohol reward; alcohol sensitivity; alcohol use disorder; allostasis; allostatic load; behavior measurement; cytokine; drinking; drinking onset; early alcohol use; early onset; injured; novel; pre-clinical; promoter; response; serotonin transporter; social stress; stressor; theories; treatment strategy

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.

描述（由申请人提供）：INIA研究人员和其他人假设压力和酒精暴露会触发适应过程，从而损伤边缘和下丘脑应激通路，并为饮酒增加创造条件。这一理论得到了美国人口流行病学研究结果的支持，即生活压力源的数量与饮酒量呈正相关，而且这些影响在早期开始饮酒的人身上最为明显。最近的研究表明，血清素转运蛋白启动子多态性和应激在预测总酒精摄入量、开始饮酒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的遗传变异也与动物和人类青少年的应激性重度饮酒有关；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，社会压力过程会增加酒精动机反应和酒精消费量，并且这种关系将被饮酒开始的年龄和所调查的基因所改变。为了验证我们的假设，不寻求治疗，有或没有酒精使用障碍的重度饮酒者将被纳入酒精解毒的临床研究单位。禁欲开始4天后，受试者将随机接受特里尔社会压力测试（TSST）或时间匹配的中性条件；皮质醇将在这些过程中被测量。在TSST或中性条件之后，将使用操作性自我管理范式提供获得酒精的机会，其中反应需求随着每次获得酒精饮料而逐渐增加；在会议结束时，会提供自制酒。我们还将使用酒精敏感性程序对受试者进行研究，该程序建立了酒精在单一疗程内对主观、生理和行为测量的剂量效应函数。研究结果将具有科学和临床的重要性，在建立遗传和环境影响的潜在机制之间的压力和酒精在重度饮酒者的关系。