Functional Analysis of GABAerglc Sedative/Anxiolytics

描述(申请人提供)：抗焦虑药物和镇静催眠药是所有精神活性药物中最广泛使用的处方之一。与它们的使用相关的滥用、滥用和生理依赖仍然令人担忧。在过去的20年里，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影响分类提供了一个动物模型。它还被证明是一种独特的灵敏和选择性的行为分析，用于检测新的化学结构、新的受体结合图谱和新的中心作用药物的细胞活性的体内功能相关性。本申请的目的是基于我们以前工作中的证据，即药物歧视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是唯一强大的。具体目的1是表征结合苯二氮卓类(BZ)位点的GABAA调节剂的体外图谱和它们的体内鉴别刺激效应图谱之间的关系。在了解GABAA受体复合体结构方面的进展导致了优先与GABAA受体亚型结合的新化合物的开发，这些化合物在调节GABA方面效率较低，或两者兼而有之。人们希望，这些化合物将成为治疗焦虑和睡眠障碍的更好药物，对长期使用产生较低的耐受性，并减少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影响提供了一个平台，我们将对此进行测试。具体目标2是测试在慢性BZ期间和之后给予谷氨酸能配体的效果与慢性BZ给药之间的关系的预测。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的过度功能。这项拟议的研究将利用药物辨别训练对药物作用神经底物的敏感性来探索谷氨酸假说对BZ戒断综合征的预测。这些数据对于我们理解苯并(口恶英)依赖的机制及其与苯并(口恶英)耐受性的关系至关重要。其中一项具体目标2下的研究将扩展我们对BZ配体的生理依赖性的工作，以直接测试使用N-甲基-D-天冬氨酸受体的非竞争性拮抗剂来改善BZ的戒断。

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.