INTERACTION OF ETHANOL WITH GABA-A RECEPTORS

乙醇与 GABA-A 受体的相互作用

• 批准号: 3112966
• 负责人: LUIS GERARDO AGUAYO
• 金额: $ 4.58万
• 依托单位: CATHOLIC UNIVERSITY OF VALPARAISO
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3112966
• 关键词: GABA receptor; adenosine triphosphate; benzodiazepine receptor; benzodiazepines; calcium; cell membrane; cerebral cortex; chlorine; cyclic AMP; developmental neurobiology; drug adverse effect; electrophysiology; embryo /fetus drug adverse effect; ethanol; gamma aminobutyrate; hippocampus; ions; laboratory mouse; laboratory rat; microelectrodes; neurons; neuropharmacology; pentobarbital; phenobarbital; spinal cord; tissue /cell culture; voltage /patch clamp; zinc

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter found throughout mammalian central nervous system. Activation of a class of postsynaptic receptors (GABAA receptors) by GABA leads to a fast and transient increase in chloride (Cl-) current that results in membrane hyperpolarization or depolarization. This membrane response is an effective mechanism to reduce postsynaptic membrane excitability as action potential firing is inhibited. The increase on Cl- conductance associated to the activation of GABA-A receptors is subject to modulation by barbiturates and benzodiazepines which can increase the Cl- conductance by acting at distinct but interacting sites on the GABA receptor- Cl- ion channel complex. Biochemical and behavioral studies have suggested that pharmacologically relevant concentrations of ethanol can potentiate the function of the GABA receptor- Cl- ion channel complex in the brain. Electrophysiological experiments at the neuronal level have found that ethanol may enhance, depress or have no effect on GABA-mediated responses suggesting cellular diversity or the existence of a complex interaction between ethanol and GABA receptors. In spite of the attempts to gain insights on this action of ethanol no information is presently available on the site of action of ethanol (glial or neuronal receptors), or on the mechanism by which ethanol may interact with the GABA-A receptor at the cellular level. The primary objective of this project is the characterization of the actions of ethanol on the GABA-activated Cl- current in mammalian hippocampal, cortical and spinal cord neurons using the patch-clamp technique. In addition, the influence of various modulators on the function of GABA-A receptors will also be investigated. Such information may be important in understanding the cellular basis for ethanol intoxication and its interaction at the cellular level with benzodiazepine and barbiturates.

γ-氨基丁酸（GABA）是一种主要的抑制性神经递质 遍布哺乳动物的中枢神经系统 类的激活 突触后受体（GABAA受体）的GABA导致快速， 氯离子（Cl-）电流瞬时增加，导致膜 超极化或去极化。 这种膜反应是一种 降低突触后膜兴奋性的有效机制， 动作电位放电被抑制。 Cl-电导的增加 与GABA-A受体的活化相关的神经元受体的活性受到调节， 巴比妥类药物和苯二氮卓类药物， 作用于GABA上不同但相互作用的位点 受体-氯离子通道复合物。 生物化学和行为研究 已经表明，乙醇的相关浓度 可增强GABA受体- Cl-离子通道复合物的功能 在大脑中。 神经元水平的电生理实验 发现乙醇可以增强、抑制或不影响 GABA介导的反应表明细胞多样性或存在 乙醇和GABA受体之间的复杂相互作用。 尽管 试图了解乙醇的这种作用， 目前可在乙醇的作用部位（神经胶质或神经元 受体），或乙醇可能与受体相互作用的机制。 GABA-A受体在细胞水平。 这项工作的主要目的是 该项目是乙醇的行动的特点， 哺乳动物海马、皮层和脊髓GABA激活的Cl-电流 脊髓神经元的膜片钳技术。 此外，影响 对GABA-A受体功能的各种调节剂的研究也将是 研究了 这些信息可能对理解 乙醇中毒的细胞基础及其在 苯二氮卓类药物和巴比妥类药物。