INTERACTION OF ETHANOL WITH GABA-A RECEPTORS

氨基丁酸(GABA)是一种主要的抑制性神经递质 广泛分布于哺乳动物的中枢神经系统。类的激活 GABA对突触后受体(GABAA受体)的影响导致快速和 导致膜的氯(Cl-)电流的瞬时增加 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。氯离子电导的增加 与激活GABA-A受体相关的受体受到调制 通过巴比妥酸盐和苯二氮卓类药物，可以增加氯- 作用于GABA上不同但相互作用的部位的电导 受体-氯离子通道复合体。生化和行为研究 已经表明，药理上相关浓度的乙醇 能增强GABA受体-氯离子通道复合体的功能 在大脑里。神经元水平的电生理实验 已经发现乙醇可能会增强、抑制或不影响 GABA介导的反应提示细胞多样性或存在 乙醇和GABA受体之间的复杂相互作用。尽管 试图深入了解乙醇的这一作用没有信息是 目前可用于乙醇的作用部位(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 细胞水平的GABA-A受体。这样做的主要目标是 该项目描述了乙醇对 哺乳动物海马、皮质和脊髓中GABA激活的氯离子电流 使用膜片钳技术的脊髓神经元。此外，它的影响 对GABA-A受体功能的各种调节剂也将 调查过了。这些信息可能对理解 乙醇中毒的细胞学基础及其相互作用 细胞水平的苯二氮卓类和巴比妥类。

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.