Moderate Human NMDA Receptor Function and Ethanol Response

家族史和嗜刺素基因型别对NMDA受体功能和酒精的影响 响应 在CTNA综述中，我们假设谷氨酸和多巴胺相互作用中的干扰 系统通过以下方式导致对酒精依赖的易感性：1)损害正常的 奖赏/激励回路，从而增加与酒精相关的相对激励影响 奖赏；以及2)通过改变N-甲基-D天冬氨酸(NMDA)谷氨酸受体的奖赏价位 乙醇的拮抗剂成分对奖励的作用，使乙醇成为一种更容易上瘾的物质 那些处于危险中的人。项目3将通过评估NMDA受体是否增加来探索后一种假设 与酒精依赖家族史相关的功能与“奖赏”的变化有关 在这项研究中，NMDA受体的功能，通过评估对 NMDA受体拮抗剂氯胺酮和乙醇反应，使用乙醇“钳制”程序评估 (将药代动力学变异性的影响降至最低)，将被确定。通过探索两者之间的关系 在氯胺酮和乙醇反应之间，我们可以检查NMDA受体拮抗的程度 有助于平衡正性(兴奋剂、快感)和负性(镇静、烦躁)的影响 乙醇，即它的奖励价。 家族酗酒史是形成酒精依赖的危险因素。一个 酗酒的家庭风险的组成部分似乎表现为奖励价的变化 乙醇效应。这项研究将检验氯胺酮和酒精反应相似的假设 受试者中受酗酒家族史的影响。如果是这样的话，这将表明可遗传因素 影响NMDA受体功能是遗传风险最重要的生物标志物之一 治疗酒精依赖。此外，这项研究将开始探索基因变异的影响 与家族饮酒易感性相关的NMDA受体功能改变 依赖。

Family History and Spinophilin Genotype Influence on NMDA Receptor Function and Ethanol Response In the CTNA Overview, we hypothesize that disturbances in the interplay of glutamate and dopamine systems contribute to the vulnerability to alcohol dependence by: 1) impairing the normal engagement of reward/motivation circuitry and thereby increasing the relative motivational impact of alcohol-related rewards; and 2) by shifting the reward valence of the N-methyl-D aspartate (NMDA) glutamate receptor antagonist component of ethanol action toward reward, making ethanol a more addictive substance for those at risk. Project 3 will explore the latter hypothesis by evaluating whether increases in NMDA receptor function associated with a family history of alcohol dependence are associated with changes in the "reward valence" of ethanol. In this study, NMDA receptor function, assessed by evaluating the response to the NMDA receptor antagonist ketamine, and ethanol response, assessed using the ethanol "clamp" procedure (to minimize the impact of pharmacokinetic variability), will be determined. By exploring the relationship between ketamine and ethanol response, we can examine the extent to which NMDA receptor antagonism contributes to the balance of the positive (stimulant, euphoric) and negative (sedative, dysphoric) effects of ethanol, i.e. its reward valence. A family history of alcoholism is a risk factor for the development of alcohol dependence. A component of the familial risk for alcoholism appears to be expressed as a change in the reward valence to ethanol effects. This study will test the hypothesis that both ketamine and alcohol response will be similarly influenced by family history of alcoholism within subjects. If so, it would suggest that heritable factors influencing NMDA receptor function contribute to one of the most important biomarkers for the heritable risk for alcohol dependence. Further, this study will begin to explore the impact of variation in genes that contribute to alterations in NMDA receptor function associated with the familial vulnerability to alcohol dependence.