Activating Effects of Ethanol in Selectively Bred Rats

描述（由申请人提供）：几十年来，酒精滥用和酒精中毒的行为和生物学表型已经在文献中被描述、调查和报道。在当代实验文献中，已经有相当多的努力来发现遗传因素，最终表现为对酒精滥用的倾向或易感性。人类和动物酒精滥用和酒精中毒模型的研究大大提高了这一领域的知识，但在许多情况下，很难在人类研究和动物研究的结果之间找到有意义的相似之处。这一建议侧重于对整体前提的评估，即酒精的强化效应反映在表型反应中，并部分由表型反应介导，这些表型包括行为（如运动）和自主神经激活。在最近的研究中，我们研究了心率（HR）作为自主神经活动的指标，它代表了酒精管理和酒精摄入后的一些独特特征（Bell等人，2002）。拟议的实验试图扩展这些发现，并测试有关酒精增强特性的行为和HR反应是否以及在多大程度上至少部分源于遗传倾向和过度饮酒的假设。另一个目标是评估这些表型特征是否可以证明是有用的，客观的措施，以评估酒精增强功效的行为和神经生物学基础的理论假设，这可能有助于药物治疗的发展。为了实现这些目标，实验将在四个特定目的中研究选择性饲养大鼠(1)乙醇给药的行为和HR剂量反应效应，(2)自由选择饮酒时自我给药乙醇的行为和HR激活效应，(3)在操作性范式中自我给药乙醇的行为和HR激活效应，旨在评估反应的预期期、消退期和恢复期。(4)直接向大脑腹侧被盖区自灌乙醇脑内的行为和HR激活效应，以评估介导这些行为表型的潜在神经生物学基质。这些发现将有助于评估、扩展和验证所提出的措施在过度寻求酒精行为的动物模型中的表型关联，并将为人类酗酒者和那些倾向于酒精滥用和酒精中毒的人的特征表型提供潜在的经验相似性。

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.