Neurochemical Bases for the Rewarding Effects of Ethanol

描述(申请人提供)：长期以来，酒精对行为的影响一直被认为依赖于伽马氨基丁酸(GABA)的神经传递。最近，GABAA受体亚型1424被提出用来调节低到中等浓度的酒精的作用。目前的提案将通过测试1424 GABAA受体介导乙醇增强特性的方面的假设来检验这种可能性，从而对乙醇的自愿摄入做出关键贡献。我们将使用病毒介导的RNA干扰来下调伏隔核中14和4个GABAA受体亚基的表达，伏隔核是参与奖赏和强化过程的大脑区域，以探讨1424 GABAA受体在大鼠饮酒行为中的作用。在我们的实验目标中，我们将测试这种受体对口服乙醇消费的贡献，以及对乙醇的仪器反应。我们还将利用体外电生理技术开始研究NAC中的乙醇与1424 GABAA受体相互作用的机制。总之，这些研究将确定GABAAR的两个独特的亚基在大脑奖励回路的主要区域NAC中在乙醇增强效应中的作用。了解调节酒精强化作用的神经机制对于开发治疗方法以辅助酒精滥用和酒精中毒的药物治疗至关重要。公共卫生相关性阐明支持饮酒的神经递质和受体系统对于了解酒精的药理作用如何导致自愿摄入酒精至关重要，包括在滥用条件下。如果在这项建议中的实验中研究的GABAA受体被发现有助于饮酒，那么未来将表明通过与该受体相互作用来减少饮酒的可能的药物方法的研究。

DESCRIPTION (provided by applicant): The behavioral effects of alcohol have long been considered to depend on gamma-amino-butyric acid (GABA) neurotransmission. Recently, the GABAA receptor isoform, 1424, has been proposed to mediate effects of alcohol at low-to-moderate concentrations. The current proposal will examine this possibility by testing the hypothesis that the 1424 GABAA receptor mediates aspects of the reinforcing properties of ethanol, thereby critically contributing to voluntary intake of ethanol. We will use viral-mediated RNA interference to knock down expression of the 14 and 4 GABAA receptor subunits in the nucleus accumbens, a brain region involved in processes of reward and reinforcement, to probe the contribution of the 1424 GABAA receptor to ethanol drinking behaviors by rats. Within our experimental aims we will test the contribution of this receptor to oral ethanol consumption, as well as to instrumental responding for ethanol. We will also initiate studies of the mechanism whereby ethanol in the NAc interacts with the 1424 GABAA receptor, using in vitro electrophysiogical techniques. Together, these studies will serve to define a role for two unique subunits of the GABAAR in a primary region of the brain reward circuitry, the NAc, in the reinforcing effects of ethanol. Understanding the neural mechanisms that mediate ethanol's reinforcing effects is critical for the development of treatments to assist in pharmacological therapies for alcohol abuse and alcoholism. PUBLIC HEALTH RELEVANCE The elucidation of the neurotransmitter and receptor systems that support alcohol drinking is critical for understanding how the pharmacological actions of alcohol lead to voluntary intake of alcohol, including under conditions of abuse. If the GABAA receptor studied in the experiments in this proposal is found to contribute to alcohol drinking, then future research on possible pharmaceutical approaches to reduce drinking by interacting with this receptor would be indicated.