Activating Effects of Ethanol in Selectively Bred Rats

描述（由申请人提供）：几十年来，文献中已经描述、研究和报告了酒精滥用和酒精中毒的行为和生物学表型。在当代的实验文献中，已经有相当大的努力来发现遗传因素，这些遗传因素最终表现为酗酒的倾向或易感性。通过对人类和酒精滥用和酒精中毒动物模型的研究，这一竞技场的知识有了相当大的进步，但在许多情况下，很难在人类研究结果和动物研究结果之间得出有意义的相似之处。该提案侧重于对以下总体前提的评估：酒精的强化作用反映在表型反应中，并部分由表型反应介导，并且这些表型包括行为（例如，运动）和自主激活。在最近的研究中，我们已经研究了心率（HR）作为自主活动的指数，其代表了酒精施用和酒精摄入后的一些独特的特征（Bell等人，2002年）。拟议中的实验试图扩展这些发现，并测试假设是否，以及在何种程度上，行为和HR反应酒精的强化性能的结果，至少部分，从遗传倾向过度饮酒自我管理。另一个目标是评估这些表型特征是否可以被证明是有用的，客观的措施，在评估理论假设的行为和神经生物学基板的酒精的强化功效，这可能有助于药物治疗的发展。为了实现这些目标，四个特定目的的实验将在选择性饲养的大鼠中研究（1）乙醇给药的行为和HR剂量反应效应，（2）自由选择饮酒中自我给药乙醇的行为和HR激活效应，（3）设计用于评估预期、消退、和反应的恢复，和（4）行为和HR激活作用的颅内自我管理乙醇直接进入大脑的腹侧被盖区，以提供一个潜在的神经生物学底物介导这些行为表型的评价。这些发现将用于评估、扩展和验证拟议的措施，作为过度饮酒行为动物模型中的表型关联，并将提供人类酗酒者和那些有酗酒和酗酒倾向的人的特征表型的潜在经验相似之处。

DESCRIPTION (provided by applicant): Behavioral and biological phenotypes of alcohol abuse and alcoholism have been described, investigated and reported in the literature for decades. In contemporary experimental literature, there has been considerable effort toward discovering hereditary factors that are ultimately expressed phenotypically as predispositions or susceptibilities to alcohol abuse. Knowledge in this arena has been advanced considerably by research both in humans and in animal models of alcohol abuse and alcoholism but, in many cases, it has been difficult to draw meaningful parallels between the findings from human studies and that of animal research. This proposal focuses on an evaluation of the overall premise that the reinforcing effects of alcohol are reflected in, and are mediated partly by, phenotypic responses, and that these phenotypes include behavioral (e.g., locomotor) and autonomic activation. In recent studies, we have investigated heart rate (HR) as an index of autonomic activity that represents some distinctive profiles consequent to alcohol administration and alcohol ingestion (Bell et al., 2002). The proposed experiments seek to extend these findings and to test hypotheses concerning whether, and the extent to which, behavioral and HR reactions to alcohol's reinforcing properties result, at least in part, from hereditary predispositions to excessive alcohol self-administration. Another goal is to assess whether these phenotypic characterizations could prove to be useful, objective measures in evaluating theoretical assumptions on the behavioral and neurobiological substrates of alcohol's reinforcing efficacy, which could assist in pharmacotherapy development. To accomplish these goals, experiments in four Specific Aims will investigate in selectively bred rats (1) behavioral and HR dose-response effects of ethanol administration, (2) behavioral and HR activating effects of self-administered ethanol in free-choice drinking, (3) behavioral and HR activating effects of self-administered ethanol in an operant paradigm designed to evaluate periods of anticipation, extinction, and recovery of responding, and (4) behavioral and HR activating effects of intracranially self-administered ethanol directly into the ventral tegmental area of the brain in order to provide an evaluation of potential neurobiological substrates mediating these behavioral phenotypes. The findings will serve to evaluate, expand and validate the proposed measures as phenotypic associations within animal models of excessive alcohol-seeking behavior and will provide potential empirical parallels of characterized phenotypes in human alcoholics and those who are predisposed to alcohol abuse and alcoholism.