Functional Analysis of GABAerglc Sedative/Anxiolytics

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。误用、滥用和与使用相关的生理依赖一直是人们关注的问题。20多年来，药物判别分析为精神活性药物主观效应分类提供了与临床前药物滥用责任评估相关的动物模型。它也被证明是一种独特的敏感性和选择性的行为分析，用于检查新的化学结构的体内功能相关性，新的受体结合谱，以及中枢作用药物的新的细胞活性。当前应用的目的是基于我们以前的工作证据，即药物鉴别分析在分析精神活性药物的生化和行为效应之间的关系方面具有独特的强大作用。特异性目的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体内区别刺激效应之间的关系。随着对GABAA受体复合物结构的了解不断深入，开发出了优先结合GABAA受体亚型、调节GABA效率较低或两者兼而有之的新型化合物。希望这些化合物能更好地治疗焦虑和睡眠障碍，减少长期使用的耐受性，减少滥用和依赖的可能性。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。具体目的2是测试预测慢性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。体外实验数据和小鼠惊厥阈值研究数据强烈表明，慢性Bz停用后出现的戒断综合征可能不是由于gaba能功能降低，而是由于嗜离子性谷氨酸能系统功能过度。本研究将利用药物识别训练对药物作用神经元底物的敏感性，探讨谷氨酸假说对Bz戒断综合征的预测。这些数据将对我们理解Bz依赖机制及其与Bz耐受性的关系至关重要。Specific Aim 2下的一项研究将扩展我们对Bz配体生理依赖性的研究，为使用n-甲基- d -天冬氨酸受体的非竞争性拮抗剂改善Bz戒断提供直接测试。

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.