Neural Basis of Ethanol Sensitization/Drinking in Mice

描述(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。在人类和酒精中毒的动物模型中，酗酒家族史是高度酒精寻求行为的有力预测因素，当一个人同时具有高酒精中毒遗传负荷和个人饮酒史时，预后更差。这项建议寻求更好地理解因酒精经历而改变的神经机制。将用于该项目的小鼠群体已经表明，行为敏感化与酒精的运动刺激效应和饮酒之间存在联系。 具体地说，这些选择性繁殖的高酒精偏好(HAP)小鼠在反复给药后更有可能对乙醇表现出运动敏感化(LMS)，这表明LMS和饮酒可能在遗传和生理上有联系。研究LMS的潜在机制可能会深入了解高酒精饮酒的机制。这一建议通过研究早期基因表达，直接寻找LMS所涉及的神经通路及其与过量饮酒的关系的证据。实验还将评估暴露在足以引发LMS的酒精中是否会增加酒精和/或饮酒的激励价值。最后，由于HAP小鼠持续的LMS需要它们将测试环境与之前的酒精注射联系在一起，因此研究将试图了解酒精的记忆是否会影响饮酒和酒精的激励价值。一项研究还将测试治疗酒精中毒的氨基己酸酯能否逆转酒精暴露引起的酒精回报价值的变化。假设是，神经和行为可塑性的联合形式是过度饮酒和LMS获得的基础，杏仁核可能是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.