Functional Analysis of GABAerglc Sedative/Anxiolytics

GABAerglc 镇静/抗焦虑药的功能分析

基本信息

批准号：
7090107
负责人：
Nancy A. Ator
金额：
$ 35.92万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-05-01 至 2008-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Anxiolytics and sedative-hypnotics are among the most widely prescribed of all psychoactive medications. Misuse, abuse, and physiological dependence associated with their use are of continuing concern. Over the past 20 years, drug discrimination analysis has provided an animal model for classification of the subjective effects of psychoactive drugs relevant to preclinical drug abuse liability assessments. It also has proven uniquely sensitive and selective as a behavioral assay for examining functional in vivo relevance of novel chemical structures, novel receptor binding profiles, and novel cellular activity for centrally acting drugs. The aims of the present application are predicated on the evidence from our previous work that drug discrimination analysis is uniquely powerful for analyzing the relationship between the biochemical and behavioral effects of psychoactive drugs. Specific Aim 1 is to characterize the relation between in vitro profiles for GABAA modulators that bind the benzodiazepine (Bz) site and their in vivo profiles of discriminative stimulus effects. Advances in understanding the structure of the GABAA-receptor complex have led to development of novel compounds that preferentially bind GABAA receptor subtypes, have lower efficacy in modulating GABA, or both. The hope is that such compounds will be better treatments for anxiety and sleep disorders, produce less tolerance with chronic use, and have less abuse liability and dependence potential. The in vitro work on these compounds provides a platform for making predictions about specific behavioral effects, which we will test. Specific Aim 2 is to test predictions about the relation between chronic Bz administration and the effects of glutamatergic ligands administered during and after the chronic Bz. In vitro data and data from studies of convulsant thresholds in mice strongly suggest that the withdrawal syndrome that emerges after discontinuation of chronic Bz use may be due less to reduced GABAergic functioning as to overfunctioning of the ionotropic glutamatergic system. The proposed studies will exploit the sensitivity of drug discrimination training for neuronal substrates of drug action to explore the predictions of the glutamate hypothesis of the Bz withdrawal syndrome. These data will be critical to our understanding of mechanisms of Bz dependence and their relation to Bz tolerance. One of the studies under Specific Aim 2 will extend our work on physiological dependence on Bz ligands to provide a direct test of the use of non-competitive antagonists for the N-methyl-D-aspartate receptor to ameliorate Bz withdrawal.

描述（由申请人提供）：抗焦虑药和镇静催眠药是所有精神活性药物中最广泛使用的药物。与其使用相关的误用、滥用和生理依赖性一直受到关注。在过去的20年里，药物歧视分析为与临床前药物滥用倾向评估相关的精神活性药物的主观影响进行分类提供了动物模型。它还被证明作为一种行为测定具有独特的敏感性和选择性，用于检查新化学结构、新受体结合谱和中枢作用药物的新细胞活性的功能体内相关性。本申请的目的基于我们之前工作的证据，即药物辨别分析对于分析精神活性药物的生化和行为影响之间的关系具有独特的强大作用。具体目标 1 是表征结合苯二氮卓 (Bz) 位点的 GABAA 调节剂的体外特征与其区分刺激效应的体内特征之间的关系。对 GABAA 受体复合物结构的了解取得进展，导致开发出优先结合 GABAA 受体亚型、调节 GABA 功效较低或两者兼而有之的新型化合物。希望此类化合物能够更好地治疗焦虑和睡眠障碍，长期使用产生较低的耐受性，并且具有较低的滥用倾向和依赖性潜力。这些化合物的体外研究为预测特定行为效应提供了一个平台，我们将对此进行测试。具体目标 2 是测试对慢性 Bz 给药与慢性 Bz 期间和之后给药的谷氨酸配体的影响之间关系的预测。体外数据和小鼠惊厥阈值研究的数据强烈表明，停止长期使用 Bz 后出现的戒断综合征可能不是由于 GABA 能功能降低，而是离子型谷氨酸能系统功能过度所致。拟议的研究将利用药物辨别训练对药物作用神经元底物的敏感性来探索 Bz 戒断综合征的谷氨酸假说的预测。这些数据对于我们理解 Bz 依赖性机制及其与 Bz 耐受性的关系至关重要。具体目标 2 下的一项研究将扩展我们对 Bz 配体的生理依赖性的工作，以提供使用 N-甲基-D-天冬氨酸受体的非竞争性拮抗剂来改善 Bz 戒断的直接测试。