CHRONIC ETHANOL, DOPAMINE ELECTROPHYSIOLOGY, AND CRAVING

对酒精的渴求是高复发率的重要因素 在禁欲期间。为了开发有效的药理作用 酒精中毒的治疗，了解神经学是很重要的 渴望的基础。我们已经证明了自发行为的减少。 腹侧被盖区多巴胺能神经元的活动 (10区)。这种减少可能是DA释放减少和 在酒精戒断期间常可观察到代谢。因为 A10多巴胺系统的激活被认为是介导脑奖赏的机制 包括乙醇在内的令人上瘾的物质，很可能这 酒精戒断后A10多巴胺能神经元活性的降低 对酒精的渴求。本申请中建议的研究意在 使用电生理方法来表征慢性阻塞性肺疾病 乙醇对A10多巴胺能神经元自发活动的影响 潜在的机制。为了了解神经适应 A10多巴胺神经元对慢性乙醇处理过程的实验研究 在特定的目标下，L被设计用来研究剂量和时程 慢性乙醇处理对AL0自发活动的影响 DA神经元将在醉酒期间和最初阶段进行检查 撤回阶段提供相应变更的信息 血液中的酒精含量。在特定目标2下的实验将检验 A10多巴胺自发活动的自然功能恢复 长时间戒断(戒断)中的神经元。结果来自 我们的初步研究表明，A1O-DA神经元失活 因为慢性乙醇治疗会引起过度的去极化， 扰乱了动作电位的产生机制。这一假设 而潜在的细胞机制将在体外进行研究 全细胞记录技术。从这项建议中获得的结果 将更好地理解慢性乙醇对A10 DA的影响 系统。更重要的是。所采用的电生理方法可以 被验证为探索可能的治疗方法的实验模型 缓解对乙醇的渴求的药物。

Craving for ethanol is an important factor for high rate of relapse during abstinence. In order to develop effective pharmacological treatment for alcoholism, it is important to understand neurological basis for craving. We have demonstrated a reduction in the spontaneous activity in dopaminergic (DA) neurons in the ventral tegmental area (area 10). This reduction may be the cause of decreased DA release and metabolism commonly observed during ethanol withdrawal period. Because activation of A10 DA system is proposed to mediate brain reward of addictive substances including ethanol, it is likely that this reduction in A10 DA neuron activity during ethanol withdrawal results in ethanol craving. The proposed studies in this application intent to use the electrophysiological approach to characterize the chronic ethanol's effects on the spontaneous activity of A10 DA neurons and the underlying mechanism. In order to understand the neuroadaptation process of A10 DA neurons to chronic ethanol treatment, experiments under Specific Aim l are designed to study the dose and time course effects of chronic ethanol treatment; The spontaneous activity of Al0 DA neurons will be examined during both the intoxication and initial withdrawal stages to provide information of corresponding changes to blood ethanol levels. Experiments under Specific Aim 2 will examine natural functional recovery of the spontaneous activity of A10 DA neurons during prolonged withdrawal period (abstinence). Results from our preliminary studies suggest that Al 0 DA neurons become inactivated because chronic ethanol treatment causes excessive depolarization which disrupts the action potential generation mechanisms. This hypothesis and the underlying cellular mechanisms will be studied with in vitro whole cell recording technique. The results obtained from this proposal will better our understanding in chronic ethanol's effects on A10 DA systems. Furthermore. the electrophysiological approach employed may be validated as a experimental model to explore possible therapeutic agents to alleviate craving for ethanol.