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: 8606722
• 负责人: MARY E MCCAUL
• 金额: $ 30.41万
• 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/8606722
• 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研究人员和其他人认为，压力和酒精暴露会触发损害边缘和下丘脑压力途径的同性恋过程，并为增加饮酒奠定了基础。该理论得到了美国人口中的流行病学发现的支持，即生命压力源与饮酒量呈正相关，并且这些影响在早期饮酒的人中最强烈。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，饮酒年龄和饮酒期间的压力的重要修饰作用。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压力诱导的大量饮酒有关。 CRH的作用一直是INIA的主要重点。我们假设，在人类实验室中，社会压力程序将增加饮酒的反应和饮酒，并且这种关系将通过饮酒年龄和正在调查的基因来改变。为了检验我们的假设，未经治疗，有或没有酒精饮酒障碍的重酒精饮用者将被送往临床研究单位进行酒精排毒。节制开始后的四天，受试者将按随机秩序，Trier社会压力测试（TSST）或时间匹配的中性条件进行。在这些过程中将测量皮质醇。在TSST或中立条件下，立即使用操作者自我管理范式提供酒精，其中响应要求随着所获得的每种酒精饮料逐渐增加；会议结束时，赚取的酒精是在交付的。我们还将使用酒精敏感性程序研究受试者，该程序在一次会议中在主观，生理和行为指标上建立剂量效应的功能。研究结果将在建立对重饮酒者压力与酒精之间关系的潜在机制方面具有科学和临床的重要性。