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 联盟的组成部分，专注于识别特定大脑神经回路中导致过量乙醇摄入的分子、细胞和行为神经适应。我们的总体假设是，扩展杏仁核回路中的遗传差异和/或神经适应是造成过度饮酒脆弱性的个体差异的原因。该部分将解决 INIA 联盟的第一个具体目标，即这些研究旨在建立动物模型，以确定与过量饮酒有关的特定大脑部位。我们建议使用两阶段方案，包括通过慢性胃内（IG）插管被动暴露于乙醇，然后进行自我输注测试程序，其中自愿摄入调味溶液与IG乙醇配对。我们第一个具体目标的总体目的是在遗传异质性大鼠和小鼠中建立和优化由依赖/戒断驱动的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注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遗传差异的假设。我们将使用具体目标 1 中建立的行为模型来表征根据乙醇饮用偏好或对乙醇戒断敏感性的已知差异而选择的各种遗传动物模型。我们还将测试至少两种在其他 INIA 站点开发的新遗传模型。最后，为了表征该模型产生的过量乙醇摄入背后的神经回路，Specific Aim 3 将检查选择性激动剂/拮抗剂直接微量输注到扩展杏仁核特定部位的效果。目标是确定影响过量乙醇摄入量和持续时间的离散大脑区域和发射系统。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导致人类酗酒的过度饮酒的神经生物学。