GABA-ERGIC DRUGS--BEHAVIORAL AND ABUSE RELATED EFFECTS

描述：（申请人摘要） 苯二氮卓类药物仍然是最常用的处方药， 自20世纪60年代以来，一直在治疗Caronic焦虑和失眠。长期使用 苯二氮卓类药物通常与身体发育有关， 依赖和成瘾，特别是在有吸毒史的人群中 或者酗酒对公共卫生后果的关注 苯二氮卓相关的身体依赖和滥用倾向导致 新型苯并二氮卓类药物研究进展 内在活性或具有受体亚型选择性。然而， 这些新化合物的药理学和行为学特征是 在其早期阶段。为了满足改进临床前方法的需求， 研究这些和未来小说的依赖性和滥用倾向 苯并二氮嗪类，研究建议，以评估激动剂的作用 在发展耐受性和依赖性方面的效力和选择性 苯二氮卓类药物首先，急性激动剂、拮抗剂或 不同苯二氮卓类药物对猴的部分激动作用 将使用三个已建立的实验进行定量评估 程序.这些实验的结果将用于功能性地 根据疗效和亚型选择性对这些药物进行分类。 同时也为后续的研究提供了实证基础。 第二，有效性和选择性在发展中的作用， 对苯二氮卓类药物的耐受性和依赖性将在 长期暴露于完全、部分或选择性激动剂的猴子。 针对疗效或选择性不同的药物的完整剂量效应函数 将在不同的慢性治疗期间确定， 关于它们的行为效应如何由此被修改的信息。的 非苯二氮卓类GABAA调节剂的行为效应也将被 检查以评估可能导致的GABAA功能的其他变化 慢性苯二氮卓类药物给药。长期研究的结果将 允许定量分析功能之间的关系 疗效或受体亚型选择性和耐受性的大小， 对苯二氮卓类药物的依赖。总体看 拟议中的研究将产生对理解 灵长类药物依赖的决定因素及成瘾预测 新型苯二氮卓类药物的责任。

DESCRIPTION: (Applicant's Abstract) Benzodiazepines have remained the most commonly prescribed drugs for the treatment of caronic anxiety and insomnia since the 1960s. Chronic use of benzodiazepines is often associated with the development of physical dependence and addiction, particularly in populations with a history of drug or alcohol abuse. Concern regarding the public health consequences of benzodiazepine-related physical dependence and abuse liability has led to the recent development of novel benzodiazopine-like agonists with low intrinsic activity or with receptor-subtype selectivity. Yet, the complete pharmacological and behavioral characterization of these novel compounds is in its early stages. To meet the need for improved preclinical methods with which to study the dependence and abuse liability of these and fututre novel benzodiazpines, studies are proposed to evaluate the roles of agonist efficacy and selectivity in the development of tolerance to and dependence on benzodiazepine-like drugs. First, the acute agonist, antagonist, or partial agonist effects of different benzodiazepine-like drugs in monkeys will be quantitatively assessed using three established experimental procedures. Results of these experiments will be used to functionally categorize these drugs on the basis of efficacy and subtype selectivity. They also will provide an empirical foundation for subsequent studies. Second, the roles of efficacy and selectivity in the development of tolerance and dependence to benzodiazopine-like drugs will be studied in monkeys that are chronically exposed to full, partial or selective agonists. Full dose-effect functions for drugs differing in efficacy or selectivity will be determined during the different chronic treatments to provide information on how their behavioral effects arc thereby modified. The behavioral effects of nonbenzodiazepine GABAA modulators also will be examined to evaluate other changes in GABAA function that may result f om chronic benzodiazepine administration. The results of chronic studies will permit a quantitative analysis of the relationship between functional efficacy or receptor-subtype selectivity and the magnitude of tolerance and dependence that develops to benzodiazepine-like drugs. Overall, the proposed research will yield knowledge essential to understanding determinants of drug dependence in primates and predicting the addiction liability of novel benzodiazopine drugs.