Neural Basis of Ethanol Sensitization/Drinking in Mice

小鼠乙醇致敏/饮酒的神经基础

• 批准号: 6970171
• 负责人: Nicholas Joseph Grahame
• 金额: $ 24.09万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-27 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6970171
• 关键词: acamprosate; alcoholic beverage consumption; alcoholism /alcohol abuse; alcoholism antagonist; amygdala; behavioral /social science research tag; behavioral habituation /sensitization; cell type; chordate locomotion; cooperative study; craving; disease /disorder model; drug /alcohol abstinence; family genetics; gene environment interaction; gene induction /repression; genetic susceptibility; immunocytochemistry; laboratory mouse; neurons; neuropsychology; regulatory gene; reinforcer; sensorimotor system

DESCRIPTION (provided by applicant): Alcoholism is caused by a complex interaction of environmental, genetic, and physiological factors. A family history of alcoholism is a strong predictor of high alcohol seeking behavior in humans and in animal models of alcoholism, and the prognosis is worse when an individual has a both high genetic load for alcoholism and a personal history of alcohol use. This proposal seeks a better understanding of neural mechanisms that are altered by alcohol experience. The populations of mice that will be used in this project already show evidence of a link between behavioral sensitization to alcohol's locomotor stimulating effects and alcohol drinking. Specifically, these selectively bred, High Alcohol Preferring (HAP) mice are more likely to show locomotor sensitization (LMS) to ethanol following repeated administration than Low Alcohol Preferring (LAP) mice, indicating that LMS and drinking are likely to be genetically and physiologically linked. Investigating mechanisms underlying LMS may yield insight into the mechanisms of high alcohol drinking. This proposal directly seeks evidence about neural pathways involved in LMS and its relationship to excessive drinking by studying immediate early gene expression. Experiments will also assess whether exposure to alcohol sufficient to induce LMS increases either the incentive value of alcohol and/or alcohol drinking. Finally, because enduring LMS in HAP mice requires that they associate their test environment with previous alcohol injections, studies will seek to understand whether the memory of alcohol affects alcohol drinking and the incentive value of alcohol. One study will also test whether acamprosate, a treatment for alcoholism, can reverse changes in the rewarding value of alcohol caused by alcohol exposure. The hypothesis is that associative forms of neural and behavioral plasticity underlie both the acquisition of excessive drinking and LMS, and that the amygdala may lie at the heart of this interaction.

描述（由申请人提供）：酒精中毒是由环境，遗传和生理因素的复杂相互作用引起的。酒精中毒的家族史是人类和酒精中毒模型中寻求行为的高饮酒行为的有力预测指标，当一个人对酒精中毒和个人使用饮酒的个人历史既有遗传负荷又具有很高的遗传负载时，预后会更糟。该建议寻求更好地理解因酒精经验而改变的神经机制。该项目中将使用的小鼠种群已经显示出证据表明行为敏化与酒精的运动刺激作用与饮酒之间的联系。 具体而言，这些有选择的育种高酒精偏爱（HAP）小鼠在重复给药后更有可能表现出对乙醇的运动敏化（LMS），而不是低酒精偏爱（LAP）小鼠，表明LMS和饮酒可能是遗传和生理上的。研究LMS的基础机制可能会深入了解高饮酒的机制。该提案直接寻求有关LMS中涉及的神经途径及其与过度饮酒的关系的证据，通过研究立即的早期基因表达。实验还将评估是否足以诱导LMS的酒精接触会增加酒精和/或饮酒的激励价值。最后，由于HAP小鼠中持久的LMS要求将其测试环境与以前的酒精注射相关联，因此研究将寻求了解酒精的记忆是否会影响饮酒和酒精的激励价值。一项研究还将测试非酗酒治疗方法是否可以逆转酒精暴露引起的酒精奖励价值的变化。假设是神经和行为可塑性的联想形式既是获得过多的饮酒和LMS的习得，又是杏仁核可能是这种相互作用的核心。