CHRONIC BARBITURATES - CNS BIOCHEMISTRY

这一建议的基本假设是中枢镇静剂，即 巴比妥酸盐，发挥了很大一部分药理作用 增强主要抑制物GABA的抑制作用 中枢神经系统中的发射器。它进一步假设，在 GABA系统对慢性用药诱导的长时程增强的影响 巴比妥酸盐是形成对苯丙氨酸耐受性的重要因素。 对这些化合物的依赖。假设有两种适应(1)a 功能性GABA受体减少和/或(2) GABA神经元的活性。作为这些适应的结果，突然 停用巴比妥酸盐将导致一段时间内GABA不足。 中枢神经系统的抑制性调节与一段高兴奋期 被证实为巴比妥酸盐禁欲综合症。一种新的GABA模型 视网膜中受体介导的抑制，高亲和力的测量 GABA结合和GABA周转的测量将是主要的 所采用的分析方法。与塞尔瓦托博士的合作努力 休斯顿的恩娜和苏珊·温特劳布博士、比尔·斯塔维诺哈博士和大卫·琼斯博士 都是在这个项目的过程中计划的。这项研究的结果 将对GABA在发育过程中的作用提供相当大的洞察力 对镇静剂巴比妥类药物的耐受性和依赖性。一些人 研究还将确定GABA在糖尿病发展中的作用。 苯二氮卓类耐受性。这些研究的结果可能会带来更好的 控制危及生命的表现的药理学方法 巴比妥酸盐戒断，并可能导致对基本的 神经化学机制参与对和/或耐受的形成 依赖巴比妥酸盐和其他中枢镇静剂。

The basis hypothesis of this proposal is that the central depressants, i.e. the barbiturates, exert a significant portion of their pharmacological effects by potentiating the inhibitory actions of GABA, a major inhibitory transmitter in the CNS. It is further hypothesized that adaptations in the GABA system to long term potentiation induced by chronic treatment with the barbiturates are important factors in the development of tolerance to and dependence on these compounds. Two adaptations are hypothesized (1) a reduction in functional GABA receptors and/or (2) a decrease in the activity of GABA neurons. As a result of these adaptations the abrupt withdrawal of the barbiturate would lead to a period of insufficient GABA inhibitory regulation in the CNS and a period of hyperexcitability evidenced as the barbiturate abstinence syndrome. A new model for GABA receptor-mediated inhibition in the retina, measurements of high affinity GABA binding and measurements of GABA turnover will be the principal analytical procedures employed. Collaborative efforts with Dr. Salvatore Enna in Houston and Drs. Susan Weintraub, Bill Stavinoha and David Jones are planned during the course of this project. The results of this study will provide considerable insight into the role of GABA in the development of tolerance to and dependence on the depressant barbiturates. Some studies will also determine the role of GABA in the development of benzodiazepine tolerance. The results of these studies may lead to better pharmacological methods for controlling the life-threatening-manifestations of barbiturate withdrawal and may lead to an understanding of the basic neurochemical mechanisms involved in the development of tolerance to and/or dependence on the barbiturates and other central depressant agents.