CHRONIC ETHANOL, DOPAMINE ELECTROPHYSIOLOGY, AND CRAVING

慢性乙醇、多巴胺电生理学和渴望

• 批准号: 2884770
• 负责人: ROH-YU SHEN
• 金额: $ 7.55万
• 依托单位: RESEARCH INSTITUTE ON ADDICTIONS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-11-01 至 1999-11-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2884770
• 关键词: GABA receptor; NMDA receptors; alcoholism /alcohol abuse; behavioral /social science research tag; brain electrical activity; brain metabolism; craving; 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.

对乙醇的渴望是高复发率的一个重要因素 禁欲期间。为了开发有效的药理 治疗酒精中毒，了解神经学很重要 贪爱的基础。我们已经证明自发性减少 腹侧被盖区多巴胺能 (DA) 神经元的活动 （10 区）。这种减少可能是 DA 释放减少的原因 乙醇戒断期间常见的代谢现象。因为 A10 DA 系统的激活被认为可以介导大脑奖赏 包括乙醇在内的成瘾物质，很可能是这样 乙醇戒断期间 A10 DA 神经元活性减少 在对乙醇的渴望中。本申请中提出的研究旨在 使用电生理学方法来表征慢性 乙醇对 A10 DA 神经元自发活动的影响 底层机制。为了理解神经适应 A10 DA 神经元对慢性乙醇处理的过程、实验 具体目标 l 旨在研究剂量和时间进程 长期乙醇治疗的影响； Al0的自发活性 DA 神经元将在中毒和初始阶段进行检查 退出阶段提供相应变化的信息 血液乙醇水平。具体目标 2 下的实验将检查 A10 DA 自发活性的自然功能恢复 长时间戒断（禁欲）期间的神经元。结果来自 我们的初步研究表明 Al 0 DA 神经元失活 因为长期乙醇治疗会导致过度去极化 破坏动作电位产生机制。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。从该提案中获得的结果 将更好地了解长期乙醇对 A10 DA 的影响 系统。此外。采用的电生理学方法可能 作为实验模型进行验证，以探索可能的治疗方法 减轻对乙醇渴望的药物。