SYNERGISTIC ACTIONS OF INTRAVENOUS ANESTHETICS

摘要 许多临床使用的镇静剂和麻醉剂通过调节γ-氨基丁酸的功能起作用 A型(GABAA)受体。GABAA受体是细胞内主要的抑制递质门控离子通道。 大脑。GABAA受体介导的抑制作用决定了大脑的整体活动，而在单个细胞中 确定细胞对给定的兴奋性输入产生动作电位的倾向。这个 GABAA受体也是包括神经活性类固醇在内的许多内源性化合物的靶标，这些化合物可以 减少静脉麻醉药的用量要求。这个项目的总体目标是调查 各种内源性化合物和临床使用的药物如何改变GABAA受体的功能 并启动麻醉的起效和解除。具体地说，我们将：i)检查绑定之间的相互作用 不同类别的GABA能麻醉药的位置；ii)检验如下假设 突触型GABAA受体参与麻醉剂的作用；iii)决定麻醉剂的效果 药物组合对天然GABAA受体功能的影响；iv)检验内源性类固醇的假说 作为协同激动剂，增强临床使用的GABA能麻醉药的行为效果；以及v)测试 竞争性类固醇拮抗剂在促进麻醉苏醒中的作用。

ABSTRACT Many clinically-used sedative and anesthetic agents act by modulating the function of the γ-aminobutyric acid type A (GABAA) receptor. The GABAA receptor is the major inhibitory transmitter-gated ion channel in the brain. Inhibition mediated by GABAA receptors sets the overall activity of the brain, while in individual cells it determines the propensity of a cell to fire an action potential in response to a given excitatory input. The GABAA receptor is also a target for numerous endogenous compounds including neuroactive steroids that can reduce the dosage requirement for intravenous anesthetics. The overall goal of this project is to investigate how various endogenous compounds and clinically used drugs modify the functioning of the GABAA receptor and initiate the onset and offset of anesthesia. Specifically, we will: i) examine the interactions between binding sites for various classes of GABAergic anesthetics; ii) test the hypothesis that modulation of tonic activity from synaptic-type GABAA receptors contributes to the actions of anesthetics; iii) determine the effects of anesthetic drug combinations on the function of native GABAA receptors; iv) test the hypothesis that endogenous steroids act as co-agonists enhancing the behavioral effects of clinically used GABAergic anesthetic drugs; and v) test the usefulness of competitive steroid-antagonists in promoting emergence from anesthesia.