ETHANOL/NEUROTRANSMITTER INTERACTIONS IN BRAIN NEURONS

这个项目的总体目标是了解乙醇如何作用于 参与奖赏中介的大脑区域，并确定如何 特定的神经递质系统改变乙醇对大脑的作用 奖励路径。作用于5-羟色胺能系统的药物会降低自愿性 实验动物和临床研究中的乙醇摄入量。这些药物 可能在大脑中与奖赏相关的区域起作用，以减少酒精渴望。这个 Tsai腹侧被盖区(VTA)对调节 奖励许多滥用药物的特性，包括乙醇。整个细胞 急性分离的多巴胺能VTA神经元的贴片记录将是 用来评估乙醇和5-羟色胺对这些细胞的作用。毒品 将在已知浓度下使用。乙醇引起大多数人的兴奋 VTA神经元在细胞外和细胞内的研究。我们已经证明了 5-羟色胺增强乙醇对VTA神经元的兴奋作用 这种作用是由5-羟色胺/2受体介导的。我们将调查这些变化 在可能参与5-羟色胺增强的特定膜电流中 酒精的影响。具体目标1是调查以下因素的影响 5-羟色胺和乙醇对钾电流的影响 自发动作电位后的超极化。具体的 我们打算研究的电流包括两种依赖钙的电流 钾电导、SK和BK、A电流(I/A)和延迟 整流器。具体目标2是确定M电流是如何降低的 受其他制剂中5-羟色胺的影响，受乙醇、5-羟色胺和 通过乙醇和5-羟色胺的结合，在VT神经元中。特定目标 #3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电流，并确定 乙醇对提高I/h的作用是否在存在时增强 5-羟色胺。从这些实验的结果来看，一个模型将是 用来描述5-羟色胺的作用之间的相互作用 乙醇对乙醇诱导的兴奋有增强作用。 这些研究应该阐明5-羟色胺的离子机制 改变乙醇在VTA中的作用。这一知识可以被利用 开发治疗酒精中毒的药物，减少酒精含量 渴望。

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.