ETHANOL/NEUROTRANSMITTER INTERACTIONS IN BRAIN NEURONS

大脑神经元中的乙醇/神经递质相互作用

• 批准号: 2871407
• 负责人: MARK S BRODIE
• 金额: $ 17.29万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2871407
• 关键词: brain; craving; ethanol; laboratory rat; membrane potentials; neuroanatomy; neurochemistry; physical chemical interaction; potassium channel; reinforcer; serotonin; voltage /patch clamp

The overall objective of this project is to understand how ethanol acts on brain areas involved in the mediation of reward, and to determine how specific neurotransmitter systems modify the action of ethanol on brain reward pathways. Drugs acting on the serotonergic system reduce voluntary ethanol intake in laboratory animals and in clinical studies. These drugs may act at brain areas involved in reward to reduce alcohol craving. The ventral tegmental areas of Tsai (VTA) is important for mediating the rewarding properties of many drugs of abuse, including ethanol. Whole cell patch recording from acutely dissociated dopaminergic VTA neurons will be used to assess the action of ethanol and serotonin on these cells. Drugs will be applied in known concentrations. Ethanol causes excitation of most VTA neurons in extracellular and intracellular studies. We have shown that serotonin potentiates the excitatory effect of ethanol on VTA neurons, and this effect is mediated by 5-HT/2 receptors. We will investigate changes in specific membrane currents which may underlies serotonin potentiation of ethanol effects. Specific Aim #1 is to investigate the effects of serotonin and ethanol on potassium currents which mediate the after hyperpolarization following spontaneous action potentials. The specific currents which we intend to examine include two calcium-dependent potassium conductances, SK and BK, A-current (I/A), and the delayed rectifier. Specific Aim #2 is to determine how M-current, which is reduced by serotonin in other preparations, is affected by ethanol, serotonin and by the combination of ethanol and serotonin, in VT neurons. Specific Aim #3 is to determine whether serotonin alters h-current (I/h), a hyperpolarization-activated inward rectifier current, and to determine whether the effect of ethanol to enhance I/h is increased in the presence of serotonin. From the results of these experiments, a model will be developed to describe the interactions between the effects of serotonin and ethanol which result in potentiation of ethanol-induced excitation. These studies should elucidate the ionic mechanisms by which serotonin alters the action of ethanol in the VTA. This knowledge could be exploited to develop drugs for the treatment of alcoholism which reduce ethanol craving.

该项目的总体目的是了解乙醇如何作用 参与奖励调解的大脑区域，并确定如何 特定的神经递质系统修改乙醇对脑的作用 奖励途径。作用于血清素能系统的药物减少了自愿 实验动物和临床研究中的乙醇摄入量。这些药物 可以在涉及奖励的大脑区域起作用，以减少渴望酒精。这 TSAI（VTA）的腹侧换段区域对于中介 包括乙醇在内的许多滥用药物的奖励特性。全细胞 从急性解离的多巴胺能VTA神经元记录的贴片记录将是 用于评估乙醇和5-羟色胺对这些细胞的作用。毒品 将以已知浓度应用。乙醇引起大多数 细胞外和细胞内研究中的VTA神经元。我们已经表明 5-羟色胺增强乙醇对VTA神经元的兴奋作用，并增强 该作用是由5-HT/2受体介导的。我们将调查更改 在可能是5-羟色胺增强基础的特定膜电流中 乙醇作用。特定目的＃1是调查 钾电流上的5-羟色胺和乙醇，介导后 自发作用电位后的超极化。具体 我们打算检查的电流包括两个依赖钙 钾电导，SK和BK，a电流（I/A），延迟 整流器。特定目的＃2是确定如何减少的M电流 通过5-羟色胺在其他制剂中，受乙醇，5-羟色胺和 VT神经元中乙醇和5-羟色胺的结合。具体目标 ＃3是确定5-羟色胺是否改变H-电流（I/H），A 超极化激活的内向整流器电流，并确定 在存在下，乙醇增强I/H的影响是否会增加 5-羟色胺。从这些实验的结果来看，模型将是 开发以描述5-羟色胺的作用之间的相互作用 和乙醇会增强乙醇诱导的兴奋。 这些研究应阐明5-羟色胺的离子机制 改变乙醇在VTA中的作用。可以利用这些知识 开发药物以治疗酗酒，以减少乙醇 渴望。