ANESTHETICS' MECHANISMS OF ACTION--PRESYNAPTIC SITES

更安全、更有效的全身麻醉药的开发已经 由于缺乏对神经元部位的了解而受到限制 行动机制。中枢神经的突触传递 系统(CNS)被认为是麻醉作用的主要靶点， 然而，只有几项研究调查了可能的突触前 行为。我们实验室的初步结果表明， 临床有效浓度的挥发性麻醉药(例如 0.5%~1.5%氟烷)促进γ-氨基丁酸的释放 来自突触前终末的酸(GABA)，其证据是 GABA介导的微小抑制性突触后电流的频率 (IPSCS)。这种突触前动作将增加已建立的后脑 氟烷引起的IPSCs突触延长，导致 突触抑制明显增加。突触抑制增加是 被认为在中枢神经系统抑郁症中起着重要作用 全身麻醉。 这项拟议研究的长期目标是定义突触 导致麻醉剂诱导的中枢神经系统抑制的作用部位。 6种临床常用麻醉药(氟烷、异氟烷、 七氟醚、戊巴比妥、异丙酚和咪达唑仑)将在 突触前功能的五项独立测量。电生理学 在大鼠海马皮层脑片上记录将与使用相结合 选择性药理探针以分离和鉴定可能的 麻醉作用的突触前部位。具体的目的是比较 麻醉作用于：1)传入纤维的兴奋性；2) 兴奋性突触的频率依赖性易化，3) GABA能中间神经元的兴奋性，4)微型频率 GABA介导的IPSCs，5)抑制性抑制的频率依赖性抑制 (GABA)突触。建议的研究将提供详细资料。 关于麻醉剂引起的突触前功能和意志的改变 有助于了解麻醉剂的作用机制； 开发更好、更安全的治疗剂的先决条件 用于全身麻醉。

The development of safer and more efficacious general anesthetics has been limited by a lack of knowledge about their neuronal sites and mechanisms of action. Synaptic transmission in the central nervous system (CNS) is regarded as a primary target of anesthetic action, however, only a few studies have investigated possible presynaptic actions. Preliminary results from our laboratory have demonstrated that clinically effective concentrations of volatile anesthetics (e.g. halothane at 0.5 to 1.5 vol %) enhance the release of gamma-aminobutyric acid (GABA) from presynaptic terminals, evidenced by an increased frequency of GABA-mediated miniature inhibitory postsynaptic currents (IPSCs). This presynaptic action would add to the well established post synaptic prolongation of IPSCs produced by halothane, resulting in a marked increase in synaptic inhibition. Increased synaptic inhibition is thought to play a significant role in the CNS depression associated with general anesthesia. The long-term goal of the proposed research is to define the synaptic sites of action which contribute to anesthetic-induced CNS depression. The actions of six clinically used anesthetics (halothane, isoflurane, sevoflurane, pentobarbital, propofol and midazolam) will be compared on five independent measures of presynaptic function. Electrophysiological recording in rat hippocampal cortex slices will be combined with the use of selective pharmacological probes to isolate and identify possible presynaptic sites of anesthetic action. The specific aims are to compare anesthetic effects on: 1) the excitability of afferent fibers, 2) the frequency-dependant facilitation at excitatory synapses, 3) the excitability of GABAergic interneurons, 4) the frequency of miniature GABA-mediated IPSCs, 5) the frequency-dependant depression of inhibitory (GABA) synapses. The proposed study will provide detailed information about anesthetic-induced alterations in presynaptic function and will contribute to an understanding of anesthetic mechanisms of action; prerequisite to the development of better and safer therapeutic agents for general anesthesia.