Functional Analysis of GABAerglc Sedative/Anxiolytics

GABAerglc 镇静/抗焦虑药的功能分析

• 批准号: 6682494
• 负责人: Nancy A. Ator
• 金额: $ 36.79万
• 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/6682494
• 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）：抗精神病药和镇静催眠药是所有精神活性药物中最广泛使用的处方药。 滥用、误用和与其使用相关的生理依赖性持续受到关注。在过去的20年里，药物歧视分析提供了一个动物模型的分类与临床前药物滥用的责任评估有关的精神活性药物的主观影响。它也被证明是一种独特的敏感性和选择性的行为测定，用于检查中枢作用药物的新化学结构、新受体结合谱和新细胞活性的体内功能相关性。本申请的目的是基于来自我们先前工作的证据，即药物辨别分析对于分析精神活性药物的生物化学和行为效应之间的关系是唯一强大的。具体目标1是表征结合苯二氮卓类（Bz）位点的GABAA调节剂的体外特征与其体内区分刺激效应特征之间的关系。在理解GABAA-受体复合物的结构方面的进展已经导致开发了优先结合GABAA受体亚型、在调节GABA中具有较低功效或两者的新型化合物。希望这些化合物能更好地治疗焦虑和睡眠障碍，长期使用产生更少的耐受性，并且具有更少的滥用倾向和依赖潜力。对这些化合物的体外研究为预测特定的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是测试关于慢性Bz给药与慢性Bz期间和之后给药的谷氨酸能配体的作用之间的关系的预测。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，而是由于离子型谷氨酸能系统功能过度。拟议的研究将利用药物辨别训练对药物作用的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。这些数据将是至关重要的，我们了解的机制BZ的依赖性和它们的关系BZ的耐受性。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改善Bz戒断的直接测试。