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。我们的首要假设是，遗传差异和/或扩展杏仁核回路中的神经适应是导致个体对过量饮酒易感性差异的原因。这一组成部分将解决INIA联盟的第一个具体目标，即这些研究旨在建立动物模型，以确定与过度饮酒有关的特定大脑部位。我们建议采用两阶段方案，包括通过慢性灌胃（IG）插管被动暴露于乙醇，然后是自我输注测试程序，其中自愿摄入调味溶液与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由依赖/戒断驱动的遗传异质性大鼠和小鼠过量乙醇摄入的动物模型。每个物种的平行研究将重点关注与慢性乙醇暴露的初始时间表和自我输液测试期间的获取相关的变量。具体目标2将解决对依赖驱动的乙醇强化敏感性的遗传差异假设。我们将使用在Specific Aim 1中建立的行为模型来描述各种遗传动物模型，这些模型是根据已知的乙醇饮用偏好或对乙醇戒断的敏感性的差异而选择的。我们还将测试至少两个在INIA其他站点开发的新遗传模型。最后，为了描述该模型产生的过量乙醇摄入的神经回路特征，Specific Aim 3将研究直接将选择性激动剂/拮抗剂微量注入延伸杏仁核的特定部位的影响。目标是确定影响过量乙醇摄入的幅度和持久性的离散脑区和传递系统。这些研究将使用大鼠，主要关注GABA-A和多巴胺系统对杏仁核中央核（CeA）和腹侧被盖区（VTA）的影响。该项目的长期目标是了解过量饮酒导致人类酒精中毒的神经生物学原理。

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.