Functional Analysis of GABAerglc Sedative/Anxiolytics

GABAerglc 镇静/抗焦虑药的功能分析

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7090107
• 关键词: GABA receptor; NMDA receptors; baboons; behavior test; behavioral /social science research tag; benzodiazepine receptor; benzodiazepines; diazepam; discrimination learning; drug addiction; drug withdrawal; glutamates; ketamine; laboratory rat; lorazepam; neuropharmacology; operant conditionings; pentobarbital; psychological reinforcement; psychopharmacology; receptor binding; sedative /hypnotic; substance abuse related behavior; tranquilizer

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）：抗焦虑药和镇静性催眠术是所有精神活性药物中最广泛规定的。 滥用，滥用和生理依赖与使用相关的依赖性一直关注。在过去的20年中，药物歧视分析为与临床前药物滥用责任评估相关的精神活性药物的主观作用分类提供了动物模型。它也被证明是一种独特的敏感性和选择性，作为一种行为测定，用于检查新型化学结构，新型受体结合谱和中心作用药物的新型细胞活性的体内相关性。本应用的目的是基于我们先前工作的证据，即药物歧视分析对于分析精神活性药物的生化和行为效应之间的关系具有独特的功能。具体目的1是表征结合苯二氮卓类（BZ）位点的GABAA调节剂的体外谱之间的关系及其对歧视性刺激效应的体内特征。理解GABAA受体复合物的结构的进步导致了优先结合GABAA受体亚型的新型化合物的发展，在调节GABA方面具有较低的功效，或两者兼而有之。希望这样的化合物将是更好地治疗焦虑和睡眠障碍，持续使用较少的耐受性，并具有较小的虐待责任和依赖潜力。这些化合物上的体外工作提供了一个平台，可以预测特定的行为影响，我们将测试。具体目的2是测试有关慢性BZ给药之间关系与慢性BZ期间和之后施用的谷氨酸能配体的影响的预测。体外数据和来自小鼠抽搐阈值的研究的数据强烈表明，停用慢性BZ使用后出现的戒断综合征可能造成的戒断综合征可能较少，这是由于GABAergic功能降低而导致离子型谷氨酸乳突瘤系统的过度功能。拟议的研究将利用药物歧视训练对药物作用的神经元底物的敏感性，以探讨BZ戒断综合征的谷氨酸假设的预测。这些数据对于我们对BZ依赖机制的理解及其与BZ公差的关系至关重要。特定目标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，以直接测试使用非竞争力拮抗剂作为N-甲基-D-天冬氨酸受体改善BZ撤离的。