FUNCTIONAL ANALYSIS OF GABAERGIC SEDATIVE/ANXIOLYTICS

描述：（申请人摘要） 安眠药和镇静催眠药，特别是苯二氮卓类（Bz）， 在所有精神药物中使用最广泛的处方药之一。 误用， 与这些药物有关的滥用和生理依赖性是 持续关注。 这些化合物中的大多数通过增强 主要抑制性神经递质GABA-氨基丁酸的传递 （GABA）。 GABA A受体结构的研究进展 复合物导致了新化合物的开发， 与受体亚型结合的能力。 同时，化合物， GABAA Bz调节位点的部分激动剂也是强有力的候选物 作为焦虑和睡眠障碍的新疗法。 希望这些 较新的化合物将具有良好的临床功效和患者可接受性， 并且还显示出对长期使用的耐受性较低，具有较低的滥用倾向， 更少的依赖潜力。 然而，很少有系统的工作， 更大的受体选择性或部分激动作用的功能相关性 已经在主观效应或药物服用的整个动物模型中完成。 一 该项目的主要目标是提供这样一个系统的 这些新药物在动物药物鉴别中的表征 程序，提供了一个高度选择性的类似人类药物 分类程序，从而作为一个模型的主观效果。 在这些程序下对新型抗焦虑药和镇静剂的评价 将继续在一个背景下，也评估在何种程度上， 程序本身可以更有选择性，并确定如何培训 变量（例如，剂量、环境）可能影响结果和解释。 将在巴比妥类药物、Bz和相关化合物之间进行比较。 一 该项目的第二个主要目标是继续调查 辨别刺激和 通过研究在一个程序下如何体验来加强药物的效果 可能会调节另一个下的行为。 这些数据对于 了解某些药物学习史可以在多大程度上 增加对药物刺激作用敏感性。 实验也将 探索镇静剂的恢复或启动现象 和抗焦虑药 这个经典的程序有希望作为一个动物模型， 复发和对毒品的渴望。 研究将测试结果的程度 从药物歧视的研究预测的行为下，这一程序。 这项研究应该为当前对刺激方式的思考提供信息。 在确定慢性吸毒方面，实行管制程序。

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.