VOLATILE ANESTHETIC INTERACTIONS WITH GABA-A RECEPTORS

挥发性麻醉剂与 GABA-A 受体的相互作用

• 批准号: 3304472
• 负责人: NEIL L. HARRISON
• 金额: $ 4.3万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-01 至 1994-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3304472
• 关键词: GABA receptor; anesthetics; animal tissue; cell membrane; drug interactions; embryo /fetus tissue /cell culture; enflurane; gas chromatography; general anesthesia; halothane; hippocampus; isoflurane; laboratory rat; membrane channels; methoxyflurane; neural inhibition; neuropharmacology; pentobarbital; synapses; voltage gated channel

Many theories have been proposed concerning the mechanisms of general anesthesia Several of these, including the lipid theory and the critical volume hypothesis, make some useful predictions but fail to illuminate the nature of the events that follow anesthetic entry into the neuronal membrane. Gamma-Aminobutyric acid (GABA) is a major inhibitory transmitter in the mammalian brain, and there is considerable evidence that enhancement of GABA-mediated inhibition is associated with sedation and anesthesia. Much research on soluble anesthetics such as barbiturates has centered on GABA-mediated synaptic inhibition mediated by GABA-A receptors. GABA-A receptors mediate an increase in Cl- conductance that underlies the 'fast' inhibitory postsynaptic potential in the brain. The GABA-A receptors are now known to be a family of heterogeneous multi sub-unit receptor proteins. These GABA-A receptors are modulated by a variety of sedative and anesthetic drugs including benzodiazepines and barbiturates. Recently, there have been preliminary reports of volatile anesthetic interactions with GABA-A receptors. The main aim of this proposal is to study the interactions of the anesthetic gases enflurane, halothane and isoflurane with GABA-A receptors. Whole-cell voltage-clamp recordings will be made from cultured rat hippocampal neurons in order to study the interactions of volatile anesthetics with GABA-A receptors. In addition, paired recordings will be made to study the effect of these agents on monosynaptic inhibitory transmission. Anesthetics will be applied to the neurons via the recording solutions, and concentrations of the anesthetics will be determined directly during the experiment by gas chromatography. The specific objectives of this project are: (1) to investigate, in a quantitative manner, the modulation of GABA-A receptors in CNS neurons by three volatile anesthetics, (2) to study the effects of these anesthetics on inhibitory synapses, (3) to study direct effects of anesthetics on neuronal membranes, and (4) to investigate the mechanism by which the anesthetics modulate GABA-A receptors. In obtaining more detailed information about the pharmacology of the GABA-A receptors, it is hoped to make a realistic assessment of the role played by GABA-A receptor mechanisms in the induction and maintenance of anesthesia by these volatile anesthetics.

已经提出了许多关于一般机制的理论 麻醉其中几种，包括脂质理论和关键 数量假设，做出一些有用的预测，但无法照亮 麻醉进入神经元之后事件的性质 膜。 γ-氨基丁酸（GABA）是一种主要的抑制 哺乳动物大脑中的发射器，有大量证据 加巴介导的抑制的增强与镇静有关 和麻醉。 许多关于可溶性麻醉药的研究，例如 巴比妥类药物以GABA介导的突触抑制为中心 由GABA-A受体。 GABA-A受体介导Cl-的增加 构成“快速”抑制性后潜能的电导 在大脑中。 GABA-A受体现在被称为 异质多亚单位受体蛋白。 这些GABA-A受体 由多种镇静剂和麻醉药物调节 苯二氮卓和巴比妥类药物。 最近，有初步 与GABA-A受体挥发性麻醉相互作用的报道。 这 该建议的主要目的是研究麻醉的相互作用 带有GABA-A受体的气体，氟烷和异氟烷。 全细胞电压钳记录将由培养的大鼠进行 海马神经元，以研究挥发性的相互作用 带有GABA-A受体的麻醉药。 此外，配对的录音将 使这些药物对单突触抑制的影响 传播。 麻醉剂将通过 记录解决方案和麻醉剂的浓度将是 直接通过气相色谱法直接确定。 这 该项目的具体目标是：（1）在 定量方式，通过CNS神经元中GABA-A受体的调节 三种挥发性麻醉剂，（2）研究这些麻醉药的作用 在抑制突触上，（3）研究麻醉药的直接影响 神经元膜和（4）研究的机制 麻醉药调节GABA-A受体。 在获得更详细的 有关GABA-A受体药理学的信息，希望 对GABA-A受体扮演的作用进行现实评估 通过这些机制诱导和维持麻醉的机制 挥发性麻醉剂。