Dependence Driven Alterations in Ethanol Reinforcement

该项目是INIA联盟的一个组成部分，专注于识别导致过量乙醇摄入的特定脑神经回路中的分子，细胞和行为神经适应。我们的总体假设是，遗传差异和/或神经适应电路的扩展杏仁核是负责个体差异的脆弱性过度饮酒。这一部分将解决INIA联盟的第一个具体目标，即，这些研究旨在建立动物模型，以确定涉及过量饮酒的特定大脑部位。我们建议使用一个两阶段的协议，涉及被动暴露于乙醇通过慢性胃内（IG）插管，然后通过自我输液测试程序，其中自愿摄入的调味溶液与IG乙醇配对。我们的第一个特定目标的总体目的是建立和优化遗传异质性大鼠和小鼠中依赖/戒断驱动的过量乙醇摄入的动物模型。在每个种属中进行的平行研究将重点关注与慢性乙醇暴露的初始时间表相关的变量以及自我输注试验期间的访问。具体目标2将解决依赖性驱动的乙醇强化的敏感性遗传差异的假设。我们将使用在具体目标1中建立的行为模型来表征根据已知的乙醇饮用偏好或对乙醇戒断的敏感性差异选择的各种遗传动物模型。我们还将测试在其他INIA站点开发的至少两个新的遗传模型。最后，为了表征该模型产生的过量乙醇摄入的神经回路，具体目标3将检查直接将选择性激动剂/拮抗剂微输注到扩展杏仁核的特定部分的影响。目的是确定离散的大脑区域和传输系统，影响过量乙醇摄入的幅度和持久性。这些研究将使用大鼠，主要关注杏仁核中央核（CeA）和腹侧被盖区（VTA）中的GABA-A和多巴胺系统影响。该项目的长期目标是了解导致人类酒精中毒的过度饮酒的神经生物学。

This project is a component of an INIA Consortium focussed on identifying the molecular, cellular, and behavioral neuroadaptations in specific brain neurocircuitry that result in excessive ethanol intake. Our overarching hypothesis is that genetic differences and/or neuroadaptations in circuitry of the extended amygdala are responsible for individual differences in vulnerability to excessive consumption of alcohol. This component will address the first Specific Aim of the INIA Consortium, i.e., these studies are intended to establish animal models to identify specific brain sites involved in excessive consumption of alcohol. We propose to use a two-phase protocol involving passive exposure to ethanol via a chronic intragastric (IG) cannula followed by a self-infusion test procedure in which voluntary ingestion of a flavored solution is paired with IG ethanol. The general purpose of our first Specific Aim is to establish and optimize an animal model of excessive ethanol intake driven by dependence/withdrawal in genetically heterogeneous rats and mice. Parallel studies in each species will focus on variables related to the initial schedule of chronic ethanol exposure and access during self-infusion testing. Specific Aim 2 will address the hypothesis of genetic differences in sensitivity to dependence-driven ethanol reinforcement. We will use the behavioral model established in Specific Aim 1 to characterize various genetic animal models selected on the basis of known differences in ethanol drinking preference or sensitivity to ethanol withdrawal. We will also test at least two new genetic models developed at other INIA sites. Finally, to characterize the neural circuitry underlying excessive ethanol intake produced by this model, Specific Aim 3 will examine effects of microinfusion of selective agonists/antagonists directly into specific parts of the extended amygdala. The goal is to identify discrete brain areas and transmitter systems that influence the magnitude and persistence of excessive ethanol intake. These studies will use rats and will focus primarily on GABA-A and dopamine system influences in the central nucleus of the amygdala (CeA) and ventral tegmental area (VTA). The long-term goal of this project is to understand the neurobiology of the excessive drinking that contributes to alcoholism in humans.