Neural Basis of Ethanol Sensitization/Drinking in Mice

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。一个家庭 在人类和动物模型中，酗酒史是高酒精寻觅行为的强烈预测因素 当一个人同时具有高酒精中毒和高遗传负荷时，预后更差。 有饮酒的个人历史。这项建议寻求更好地理解神经机制，这些机制 被酒精的经历改变了。将在这个项目中使用的老鼠数量已经显示出 行为敏感化与酒精的运动刺激效应和饮酒之间的联系。 具体地说，这些选择性繁殖的高酒精偏好(HAP)小鼠更有可能表现出运动 重复给药后对乙醇的敏化(LMS)作用优于低酒精性(LAP)小鼠， 这表明LMS和饮酒很可能在基因和生理上有联系。调查 LMS的潜在机制可能有助于深入了解高酒精饮酒的机制。这项建议 直接寻找LMS涉及的神经通路及其与过量饮酒关系的证据 研究即刻早期基因表达。实验还将评估接触酒精是否 足以诱发LMS的人会增加酒精和/或饮酒的激励价值。最后， 因为在HAP小鼠身上忍受LMS需要他们将测试环境与先前的酒精联系在一起 通过注射，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是否可以 逆转酒精暴露引起的酒精回报价值的变化。假设是这样的 神经和行为可塑性的联合形式是过度饮酒和 杏仁核可能是这种相互作用的核心。

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 population 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. Experments 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.