CHRONIC ETHANOL, DOPAMINE ELECTROPHYSIOLOGY, AND CRAVING

慢性乙醇、多巴胺电生理学和渴望

• 批准号: 6198486
• 负责人: ROH-YU SHEN
• 金额: $ 2.25万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 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 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6198486
• 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.

对酒精的渴望是高复发率的重要因素 在禁欲期间为了开发有效的药理学 治疗酒精中毒，重要的是要了解神经 渴望的基础。我们已经证明了自发的 腹侧被盖区多巴胺能（DA）神经元的活动 (area 10）。这种减少可能是DA释放减少的原因， 在乙醇戒断期通常观察到代谢。因为 A10 DA系统的激活可能介导了脑内 包括乙醇在内的成瘾物质，很可能 乙醇戒断过程中A10 DA神经元活性的降低 酒精的渴望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能神经元自发活动的影响 潜在机制为了了解神经适应 A10 DA神经元对慢性乙醇处理的反应过程 在特定目标下，设计用于研究剂量和时间过程 慢性乙醇处理的影响; A1 0 DA神经元将在中毒和初始 退出阶段，以提供相应变更的信息， 血液中的酒精含量具体目标2下的实验将检查 A10 DA自发活动的自然功能恢复 神经元在长期的戒断期（禁欲）。结果 我们的初步研究表明，A1 0 DA神经元失活 因为慢性乙醇处理引起过度去极化， 破坏了动作电位的产生机制这一假设 并将在体外研究潜在的细胞机制， 全细胞记录技术从这一建议中获得的结果 将更好地了解慢性乙醇对A10 DA的影响 系统.此外。所采用的电生理学方法可以 作为一种实验模型来探索可能的治疗方法， 缓解对乙醇的渴望。