Dependence Driven Alterations in Ethanol Reinforcement

乙醇强化中的依赖性驱动的改变

• 批准号: 6449656
• 负责人: CHRISTOPHER L CUNNINGHAM
• 金额: $ 25.11万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-27 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6449656
• 关键词: GABA receptor; alcoholic beverage consumption; alcoholism /alcohol abuse; amygdala; behavior test; behavioral /social science research tag; behavioral genetics; cooperative study; disease /disorder model; dopamine; dopamine receptor; drug withdrawal; ethanol; gamma aminobutyrate; genetically modified animals; laboratory mouse; laboratory rat; model design /development; preference; reinforcer; self medication; tegmentum

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.

该项目是INIA联盟的一个组成部分，重点是鉴定特定脑神经循环中的分子，细胞和行为神经适应，从而导致过度乙醇摄入。我们的总体假设是，扩展杏仁核电路中的遗传差异和/或神经适应性是导致过度消费酒精消耗的个体差异。该组成部分将解决INIA财团的第一个特定目的，即，这些研究旨在建立动物模型，以识别与酒精过量消费有关的特定大脑部位。我们建议使用涉及通过慢性胃内（IG）套管被动暴露于乙醇的两阶段方案，然后进行自发输入测试程序，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的的一般目的是建立和优化由遗传异质大鼠和小鼠依赖/戒断驱动的过度乙醇摄入的动物模型。在每个物种中的平行研究将集中于与慢性乙醇暴露和自输入测试期间访问的初始时间表有关的变量。具体目标2将解决对依赖性驱动乙醇增强敏感性的遗传差异的假设。我们将使用特定目标1中建立的行为模型来表征根据已知乙醇饮用饮酒偏好或对乙醇戒断敏感性的已知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度乙醇摄入的神经回路，特定的目标3将检查选择性激动剂/拮抗剂的微灌注的影响，直接直接进入扩展的杏仁核的特定部分。目的是确定影响过度乙醇摄入量的大小和持久性的离散大脑区域和发射机系统。这些研究将使用大鼠，并主要集中于GABA-A和多巴胺系统在杏仁核中央核（CEA）和腹侧侧面区域（VTA）中的影响。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。