FUNCTIONAL ANALYSIS OF GABAERGIC SEDATIVE/ANXIOLYTICS

描述：(申请人摘要) 抗焦虑药物和镇静催眠药，特别是苯二氮卓类(BZ)， 在所有精神活性药物中，最广泛的处方之一。滥用， 滥用，以及与这些药物相关的生理依赖 持续的担忧。这些化合物中的大多数通过促进 主要抑制性神经递质GABA-氨基丁酸的传递 (GABA)。了解GABA受体结构的最新进展 络合物导致了更具选择性的新化合物的开发 与该受体的亚型结合。同时，化合物是 GABAA BZ调节位点的部分激动剂也是强有力的候选者 作为治疗焦虑和睡眠障碍的新疗法。希望是这些 较新的化合物将具有良好的临床疗效和患者的接受性， 对长期使用也表现出较少的容忍度，较少的滥用责任和 更少的依赖潜力。然而，几乎没有系统地研究 更大的受体选择性或部分激动性的功能相关性 已经在主观影响或吸毒的整个动物模型中进行了研究。一 该项目的主要目标是提供这样一种系统的 这些新型药物在动物药物鉴别中的表征 程序，它提供了一种高度选择性的人类药物类似物 分类程序，并因此作为主观效果的模型。 在这些步骤下对新型抗焦虑药物和镇静剂的评价 将在评估的情况下继续进行， 程序本身可以变得更有选择性，并决定如何进行培训 变量(例如，剂量、背景)可能会影响结果和解释。 将对巴比妥酸盐、BZ和相关化合物进行比较。一个 该项目的第二个主要目标是继续调查 歧视性刺激和非歧视刺激之间可能的相互关系 通过研究如何在一种程序下体验来增强药物的效果 可能会在另一种情况下调节行为。这些数据对以下方面很重要 了解某些药物学习史可以在多大程度上 增加对药物刺激效应的敏感度。实验也将 探索与镇静剂有关的恢复或启动现象 还有抗焦虑药。这种经典的手术有希望成为一种动物模型。 旧病复发和吸毒成瘾。研究将测试结果在多大程度上 从毒品歧视研究中预测在这一程序下的行为。 这项研究应该会为当前对刺激方式的思考提供信息 控制程序在确定慢性吸毒的过程中起作用。

DESCRIPTION: (Applicant's Abstract) Anxiolytics and sedative-hypnotics, particularly benzodiazepines (Bz), are among the most widely prescribed of all psychoactive medications. Misuse, abuse, and physiological dependence associated with these drugs are of continuing concern. The majority of these compounds act by enhancing transmission of the major inhibitory neurotransmitter gaba-aminobutyric acid (GABA). Recent advances in understanding the structure of the GABAAreceptor complex have led to development of novel compounds that are more selective in binding to subtypes of that receptor. Concurrently, compounds that are partial agonists at the GABAA Bz modulatory site also are strong candidates as new treatments for anxiety and sleep disorders. The hope is that these newer compounds will have good clinical efficacy and patient acceptability, and also show less tolerance with chronic use, have less abuse liability and less dependence potential. However, little systematic work on the functional relevance of greater receptor selectivity or partial agonism has been done in whole animal models of subjective effects or drug-taking. One major objective of the project is to provide such a systematic characterization of these novel agents in animal drug discrimination procedures, which provide a highly selective analog to a human drug categorization procedure, and thus serve as a model of subjective effects. The evaluation of novel anxiolytics and sedatives under these procedures will proceed in a context of also evaluating the extent to which the procedure itself can be made more selective and to determine how training variables (e.g., dose, context) may influence results and interpretation. Comparisons will be made among barbiturates, Bz, and related compounds. A second major objective of the project is to continue investigation of the possible interrelationships between the discriminative stimulus and reinforcing effects of drugs by studying how experience under one procedure may modulate behavior under the another. Such data are important for understanding the extent to which certain drug learning histories can increase sensitization to drug stimulus effects. Experiments also will explore the reinstatement, or priming, phenomenon with respect to sedatives and anxiolytics. This classic procedure has promise as an animal model of relapse and of drug craving. Studies will test the extent to which results from drug discrimination studies predict behavior under this procedure. This research should inform current thinking over the ways in which stimulus control processes operate in determining chronic drug-taking.