VOLATILE ANESTHETIC ACTIONS ON SYNAPTIC GABAA RECEPTORS

描述：（改编自申请人摘要）初步 研究中，研究者观察到两种挥发性麻醉剂 对两种生理上不同的和解剖上不同的 海马CA 1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/快速和 树突状GABAA/缓慢，介导抑制爆发活动， 双脉冲抑郁症，分别，因此可能有不同的 功能性作用，分别与癫痫发作和学习有关。 初步结果表明，全身麻醉药能够增强 GABA的功能丧失的条件下，其中的环境， 通道的细胞内侧发生了变化， 麻醉剂对GABA通道的这种独特作用是由于 细胞内作用 在目前的研究中，皮尔斯博士建议测试 这两种GABA电流的特异性作用可能解释了 药物之间的一些临床差异，并将结果扩展到 分子水平。 在3个具体目标中，他将（1）检验假设， 挥发性麻醉剂的单独的遗忘和惊厥特性， 相关的代理是由它们对这两个代理的特定操作产生的。 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;（3）识别细胞内因子 必要的麻醉诱导的变化，并定义其作用。 方法包括细胞外和全细胞破裂的补丁记录， 海马切片和单通道记录从切除的补丁， 切片和HEK 293细胞，其中GABAA受体已被 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.