VOLATILE ANESTHETIC ACTIONS ON SYNAPTIC GABAA RECEPTORS

描述：(改编自申请人的摘要)初稿 研究人员观察到，两种挥发性麻醉剂对 在生理和解剖上截然不同的两种药物上的特定作用 在海马CA1区锥体细胞中分离的GABAA受体；他有 提供了证据表明这些电流，细胞体GABAA/FAST和 树枝状GaBAA/慢速、中度抑制爆裂活性和 成对脉搏抑制，因此可能有不同的 分别在癫痫发作和学习方面发挥作用。 初步结果表明，全身麻醉药的能力增强 GABA功能在以下情况下丧失： 改变了细胞内通道的一侧，这导致了这样的说法 麻醉剂对GABA通道的这种独特作用是由于 细胞内的作用。在目前的研究中，皮尔斯博士建议测试 假设药剂对两种GABA电流的特定影响可以解释 的一些临床差异，并将结果推广到 分子水平。在三个具体目标中，他将(1)检验假设 挥发性麻醉药和挥发性麻醉剂的单独遗忘和惊厥特性 相关代理是由于它们对这两个代理的特定操作而产生的 电流通过将该系列扩展到包括两个 实验化合物；(2)检查麻醉剂的作用机制 改变通道动力学参数；以及(3)确定细胞内因素 对于麻醉剂诱导的改变是必要的，并确定它们的作用。 方法包括细胞外和全细胞破裂的斑块记录 海马区切片和来自切除的斑块的单通道记录 切片和来自HEK293细胞的GABAA受体已经被 表达。

DESCRIPTION: (Adapted from the applicant's abstract) In preliminary studies, the investigator has observed that two volatile anesthetics exert agent-specific actions on two physiologically distinct and anatomically segregated GABAA receptors in hippocampal CA1 pyramidal cells; he has provided evidence that these currents, the cell body GABAA/fast and the dendritic GABAA/slow, mediate suppression of bursting activity and paired-pulse depression, respectively, and thus may have different functional roles with respect to seizures and learning respectively. Preliminary results in which the ability of general anesthetics to enhance GABA function is lost under conditions in which the milieu of the intracellular side of the channel is changed have led to the suggestion that this unique effect of anesthetics on the GABA channel is due to an intracellular action. In the present study Dr. Pearce proposes to test the hypothesis that agent-specific effects on the two GABA currents may account for some clinical differences among agents, and to extend the results to the molecular level. In 3 specific aims, he will (1) test the hypothesis that the separate amnestic and convulsant properties of volatile anesthetics and related agents result from their agent-specific actions on these two currents by extending the series to additional agents including two experimental compounds; (2) examine the mechanisms by which anesthetics alter channel kinetic parameters; and (3) identify the intracellular factors necessary for anesthetic-induced alterations and define their roles. Methods include extracellular and whole cell ruptured patch recording in hippocampal slice, and single channel recordings from excised patches from the slice and from HEK293 cells in which GABAA receptors have been expressed.