Ethanol, NMDA Receptor and Dopamine Interactions

描述（由申请人提供）：介导乙醇致醉和增强作用的细胞机制尚不清楚。乙醇的许多神经靶点之一是兴奋性谷氨酸受体的NMDA亚型。许多研究表明，乙醇急性抑制NMDA受体功能。这种抑制作用可能与对乙醇效应的行为敏感性有关。此外，抑制NMDA受体功能已被证明能提高多巴胺（DA）系统的活性。大量证据支持这一假设，即增加中脑边缘DA系统的活动是许多药物滥用，包括乙醇的增强效果的重要组成部分之一。NMDA受体的抑制导致几个脑区中的DA系统激活。有趣的是，很少有研究表明，乙醇抑制NMDA受体可能在升高DA水平中发挥核心作用。指导这项研究的总体假设是，乙醇抑制NMDA受体活性可能是一个重要的机制，通过乙醇提高多巴胺在丘脑核。用于检验这一假设的主要方法包括对正常（野生型）小鼠和NMDA受体遗传缺陷小鼠急性和慢性给予MK-801和乙醇后DA功能的微透析和伏安法研究。这些NMDA受体功能降低的模型将用于评估成瘾相关脑区（中脑核）中多巴胺系统的功能。从这些研究中，我们希望能够深入了解酒精作用的受体机制。

DESCRIPTION (provided by applicant): The cellular mechanisms that mediate the intoxicating and reinforcing effects of ethanol are not clearly understood. One of the many neuronal targets of ethanol is the NMDA subtype of excitatory glutamate receptors. Many studies have demonstrated that ethanol acutely inhibits NMDA receptor function. This inhibition may be involved in behavioral sensitivity to ethanol effects. In addition, inhibition of NMDA receptor function has been shown to elevate dopamine (DA) system activity. Considerable evidence supports the hypothesis that increased mesolimbic DA system activity is one of the important components of the reinforcing effects of many drugs of abuse, including ethanol. Inhibition of NMDA receptors leads to DA system activation in several brain areas. Interestingly, few studies have demonstrated that ethanol inhibition of NMDA receptors may play a central role in elevating DA levels. The overall hypothesis guiding this research is that ethanol inhibition of NMDA receptor activity may represent an important mechanism through which ethanol elevates DA in the nucleus accumbens. The main approaches to be used to test this hypothesis include microdialysis and voltammetry studies of DA function following acute and chronic administration of MK-801 and ethanol to normal (wild-type) mice and mice with a genetic deficit in NMDA receptors. These models of reduced NMDA receptor function will be used to evaluate dopamine system function in an addiction-related brain area, the nucleus accumbens. From these studies we hope to gain insights into the receptor mechanisms involved in alcohol action.