Ethanol, NMDA Receptor and Dopamine Interactions

描述(由申请人提供)：调节乙醇的醉人和增强效应的细胞机制尚不清楚。酒精的众多神经元靶点之一是兴奋性谷氨酸受体的NMDA亚型。许多研究表明，乙醇能显著抑制NMDA受体的功能。这种抑制可能与行为对酒精的敏感性有关。此外，抑制NMDA受体功能可提高多巴胺(DA)系统的活性。相当多的证据支持这一假设，即中脑边缘DA系统活性的增加是包括乙醇在内的许多滥用药物强化效应的重要组成部分。抑制NMDA受体导致几个脑区DA系统的激活。有趣的是，很少有研究表明，乙醇对NMDA受体的抑制可能在提高DA水平方面发挥核心作用。指导本研究的总体假设是，乙醇抑制NMDA受体活性可能是乙醇升高伏核DA的一个重要机制。用于验证这一假说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长期给予MK-801和乙醇后DA功能的微透析和伏安研究。这些NMDA受体功能降低的模型将被用来评估与成瘾相关的大脑区域伏隔核中的多巴胺系统功能。通过这些研究，我们希望对酒精作用的受体机制有更深入的了解。

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.