CHRONIC ETHANOL, DOPAMINE ELECTROPHYSIOLOGY, AND CRAVING

慢性乙醇、多巴胺电生理学和渴望

• 批准号: 2000322
• 负责人: ROH-YU SHEN
• 金额: $ 10.14万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2000322
• 关键词: GABA receptor; NMDA receptors; alcoholism /alcohol abuse; brain electrical activity; brain metabolism; dopamine; drug addiction; drug withdrawal; electrodes; electrophysiology; laboratory rat; membrane activity; membrane potentials; neural transmission; neurochemistry; neurons; neuroregulation; neurotransmitter metabolism; receptor sensitivity; single cell analysis; stereotaxic techniques; tegmentum; voltage /patch clamp

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.

渴望乙醇是高复发率的重要因素 戒酒期间。为了开发有效的药理 酗酒的治疗，了解神经学很重要 渴望的基础。我们已经证明了自发的减少 在腹侧对段区域的多巴胺能（DA）神经元中的活性 （区域10）。这种减少可能是DA释放减少的原因，并且 通常在乙醇戒断期间观察到代谢。因为 提出了激活A10 DA系统的激活来调解大脑的奖励 包括乙醇在内的成瘾性物质，这很可能 乙醇提取结果期间A10 DA神经元活性的降低 在乙醇渴望中。在此应用中提出的研究意图 使用电生理方法来表征慢性 乙醇对A10 DA神经元自发活动的影响和 基本机制。为了理解神经适应 A10 DA神经元与慢性乙醇处理的过程，实验 在特定的目标下，L旨在研究剂量和时间课程 慢性乙醇治疗的影响； AL0的自发活动 在中毒和初始中，将检查DA神经元 提取阶段以提供相应更改的信息 血液乙醇水平。特定目标下的实验2将检查 A10 DA自发活性的自然功能恢复 长时间戒断期（禁欲）的神经元。结果 我们的初步研究表明，Al 0 DA神经元被灭活 因为慢性乙醇处理会导致过度去极化 破坏动作潜在的生成机制。这个假设 并将在体外研究潜在的细胞机制 全细胞记录技术。从本提案中获得的结果 将更好地理解慢性乙醇对A10 DA的影响 系统。此外。使用的电生理方法可能 被证实为实验模型，以探索可能的治疗 减轻对乙醇的渴望的特工。