Neural Basis of Ethanol Sensitization/Drinking in Mice

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动物模型中高度酒精寻求行为的强有力预测因素，当一个人既有酒精中毒的高遗传负荷又有酒精使用的个人历史时，预后更差。这项提案旨在更好地了解酒精经验改变的神经机制。将用于该项目的小鼠群体已经显示出对酒精运动刺激作用的行为敏感性与饮酒之间存在联系的证据。 具体而言，这些选择性繁殖的高酒精偏好（HAP）小鼠在重复给药后比低酒精偏好（HAP）小鼠更有可能表现出对乙醇的运动敏感性（LMS），表明LMS和饮酒可能在遗传和生理上相关。研究LMS的潜在机制可能会深入了解大量饮酒的机制。该提案通过研究即刻早期基因表达直接寻求有关LMS相关神经通路及其与过量饮酒关系的证据。实验还将评估是否暴露于足以诱导LMS的酒精会增加酒精和/或饮酒的激励价值。最后，由于HAP小鼠的LMS要求它们将测试环境与之前的酒精注射联系起来，因此研究将试图了解酒精的记忆是否会影响饮酒以及酒精的激励价值。一项研究还将测试阿坎酸，一种治疗酒精中毒的药物，是否可以逆转酒精暴露引起的酒精奖励价值的变化。该假说认为，神经和行为可塑性的关联形式是过量饮酒和LMS获得的基础，而杏仁核可能位于这种相互作用的核心。

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.