GABA-ERGIC DRUGS--BEHAVIORAL AND ABUSE RELATED EFFECTS

GABA 能药物——行为和滥用相关影响

• 批准号: 2770167
• 负责人: CAROL A PARONIS
• 金额: $ 10.24万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2770167
• 关键词: Saimiri; behavior test; benzodiazepine receptor; discrimination learning; dosage; drug abuse; drug tolerance; electrostimulus; gamma aminobutyrate; ligands; midazolam; neurotransmitter agonist; neurotransmitter antagonist; psychopharmacology; stimulus /response

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.

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 年代以来治疗卡罗尼克性焦虑和失眠。长期使用 苯二氮卓类药物通常与身体发育有关 依赖性和成瘾性，尤其是有吸毒史的人群 或酗酒。对公共卫生后果的担忧 与苯二氮卓相关的身体依赖性和滥用倾向导致 新型苯二氮卓类激动剂的最新进展 内在活性或具有受体亚型选择性。然而，完整的 这些新化合物的药理学和行为特征是 处于早期阶段。为了满足改进临床前方法的需要 研究这些和未来小说的依赖和滥用倾向 苯二氮卓类药物，建议进行研究以评估激动剂的作用 耐受性和依赖性发展中的功效和选择性 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子的部分激动作用 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 根据疗效和亚型选择性对这些药物进行分类。 它们也将为后续研究提供实证基础。 二、功效和选择性在发展中的作用 将研究对苯二氮卓类药物的耐受性和依赖性 长期暴露于完全、部分或选择性激动剂的猴子。 功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以提供 关于如何改变他们的行为影响的信息。这 非苯二氮卓类 GABAA 调节剂的行为影响也会 检查以评估可能导致的 GABAA 功能的其他变化 长期服用苯二氮卓类药物。长期研究的结果将 允许对功能之间的关系进行定量分析 功效或受体亚型选择性以及耐受性的程度和 对苯二氮卓类药物产生依赖性。总体而言， 拟议的研究将产生理解所必需的知识 灵长类药物依赖的决定因素和成瘾预测 新型苯二氮卓类药物的责任。