NEUROCHEMISTRY OF ALCOHOL PREFERENCE

这项建议的总体目的是进一步了解神经和行为机制参与遗传的倾向酗酒。此外，该提案旨在确定以前的酒精经验可能与高酒精消费倾向相互作用的神经和行为影响。 该提案将培训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HAP）小鼠，其沿着它们的复制系和对照系，由于选择性育种，在自由选择的酒精消耗方面有很大差异。该提案的一个目的是确定这些小鼠是否表现出神经化学的先天差异：以前的研究结果表明，表现出高酒精消耗的人类和动物可能缺乏多巴胺能和/或多巴胺能功能。为此，将使用单胺及其代谢物的组织水平分析以及选定单胺相关受体和转运蛋白的定量放射自显影。研究还将确定这些小鼠在静脉内自我给药酒精方面是否不同。这个过程是衡量酒精的奖励效应的一个指标，它不受对酒精味道敏感性的任何潜在遗传差异的影响;我们的期望是HAP小鼠更有可能通过静脉注射自我管理酒精。初步数据表明，HAP，但不是HAP小鼠表现出对酒精的运动敏感性，允许测试的假设，即酒精的运动激活作用的敏感性与神经化学和奖励的变化。为了确定HAP与LAPs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HAP小鼠接受等量的酒精，另一种是HAP小鼠自由饮酒。研究将评估酒精经验对单胺能神经化学和酒精的奖励作用的影响，通过条件性位置偏好测量，在两条线上。我们的假设，基于自发活动的数据，是HAP小鼠将显示出对酒精奖励效应的敏感性增加，而HAP小鼠则不会。 进一步的研究将确定HAP小鼠的自由选择酒精消费是否会导致行为和神经化学的类似变化。 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.