NEUROCHEMISTRY OF ALCOHOL PREFERENCE

本研究的总体目的是进一步了解酒精中毒倾向遗传的神经和行为机制。此外，该研究还试图确定先前饮酒经历对神经和行为的影响，这些影响可能与高饮酒量的倾向相互作用。这项建议将训练主要研究者使用神经化学和神经药理学技术。为了研究酒精相关性状的差异，这项工作将使用高酒精偏好和低酒精偏好（HAP和LAP）小鼠，以及它们的复制和对照系，由于选择性繁殖，在自由选择酒精摄入量方面存在很大差异。该提议的一个目的是确定这些小鼠是否在神经化学方面表现出先天的差异：先前的研究结果表明，人类和动物表现出高酒精摄入量可能缺乏血清素和/或多巴胺能功能。为此，将分析单胺及其代谢物的组织水平，并对选定的单胺相关受体和转运体进行定量放射自显影。研究还将确定这些小鼠在静脉注射酒精方面是否存在差异。这一过程是对酒精奖励效果的一种测量，这种效果不受对酒精味道敏感性的任何潜在遗传差异的影响；我们的预期是，HAP小鼠将更有可能自我静脉注射酒精。初步数据表明，HAP小鼠而LAP小鼠对酒精表现出运动致敏性，从而验证了对酒精运动激活效应的致敏性与神经化学和奖励变化相关的假设。为了确定HAP小鼠与LAP小鼠在酒精体验如何影响酒精敏感性方面是否不同，将进行两种实验：一种是HAP小鼠和LAP小鼠接受等量的酒精，另一种是HAP小鼠自由饮酒。研究将评估酒精体验对单胺能神经化学的影响，以及酒精的奖励效应，这两方面都是通过条件位置偏好来衡量的。基于运动活动数据，我们的假设是，HAP小鼠会对酒精的奖励效果表现出更高的敏感性，而LAP小鼠则不会。进一步的研究将确定在HAP小鼠中自由选择饮酒是否会导致类似的行为和神经化学变化。总的来说，通过增加对过度饮酒的神经、遗传和行为机制的基础知识，这些研究可能会进一步发展以药物为基础的酒精中毒治疗。

The overall purpose of this proposal is to further understanding of the neural and behavioral mechanisms involved in the inheritance of a predisposition towards alcoholism. Additionally, this proposal seeks to identify neural and behavioral effects of previous alcohol experience that might interact with a predisposition towards high alcohol consumption. This proposal will train the principle investigator to use neurochemical and neuropharmacological techniques. To study differences in alcohol- related traits, this work will use High- and Low- Alcohol Preferring (HAP and LAP) mice which, along with their replicate and control lines, greatly differ in free-choice alcohol consumption as a result of selective breeding. One aim of the proposal is to determine whether these mice-show innate differences in neurochemistry: previous findings have indicated that humans and animals that show high alcohol consumption may be deficient in serotonergic and/or dopaminergic function. To that end, analysis of tissue levels of monoamines and their metabolites, and quantitative autoradiography for selected monoamine-related receptors and transporters will be used. Studies will also determine whether these mice differ in intravenous self-administration of alcohol. This procedure is a measure of alcohol's rewarding effects that is not influenced by any potential genetic differences in sensitivity to the taste of alcohol; our expectation is that HAP mice will be more likely to self-administer alcohol intravenously. Preliminary data indicating that HAP but not LAP mice show locomotor sensitization to alcohol allows testing of the hypothesis that sensitization to the locomotor-activating effects of alcohol is correlated with changes in neurochemistry and reward. To determine whether HAPs differ from LAPs in how alcohol experience affects alcohol sensitivity, two kinds of experiments will be done: ones in which both HAP, and LAP mice receive equal amounts of alcohol, and ones in which HAP mice freely consume alcohol. Studies will assess effects of alcohol experience on monoaminergic neurochemistry and on the rewarding effects of alcohol, as measured by conditioned place preference, in both lines. Our hypothesis, based on the locomotor activity data, is that HAP mice will show increased sensitivity to the rewarding effects of alcohol, whereas LAP mice will not. Additional studies will determine whether free-choice alcohol consumption in HAP mice causes similar changes in behavior and neurochemistry. Overall, by increasing basic knowledge of neural, genetic, and behavioral mechanisms underlying excessive drinking, these studies may further development of drug-based treatments for alcoholism.