CHRONIC BENZODIAZEPINES--BEHAVIOR AND NEUROCHEMISTRY

慢性苯二氮卓类药物——行为和神经化学

• 批准号: 2117528
• 负责人: DAVID J GREENBLATT
• 金额: $ 21.44万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-30 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2117528
• 关键词: GABA receptor; alprazolam; anticonvulsants; benzodiazepines; brain metabolism; carbamazepine; clonazepam; dosage; drug abuse chemotherapy; drug addiction; drug addiction antagonist; drug tolerance; drug withdrawal; genetic transcription; immunocytochemistry; in situ hybridization; laboratory mouse; lorazepam; messenger RNA; molecular cloning; neurochemistry; northern blottings; psychopharmacology; radiotracer; receptor expression; stimulant /agonist; tissue /cell culture; triazolam

Benzodiazepines are the most frequently prescribed psychotropic medications in the U.S. and internationally. Clinical use of these drugs is limited by the development of tolerance and physical dependence. In addition, there is evidence for substantial benzodiazepine abuse, and dependence may contribute to this abuse. The mechanisms underlying benzodiazepine tolerance and dependence remain uncertain. Over the prior phase of this proposal, we have developed a model of benzodiazepine tolerance and withdrawal in the mouse, and have characterized in detail alterations at the GABAA receptor complex in this model. In brief, benzodiazepine agonist administration is associated with behavioral tolerance and receptor downregulation; discontinuation is associated with a transient behavioral withdrawal syndrome coincident with receptor upregulation. Chronic antagonist and inverse agonist administration also are associated with receptor upregulation. Chronic antagonist and inverse agonist administration also are associated with receptor upregulation. In addition, we have developed an in vitro system to assess benzodiazepine effects on cultured cortical neurons. Results in general parallel those obtained in vivo. The present proposal represents an extension of these models in two major areas: 1. Molecular biological methods; and 2. Pharmacological interventions to limit tolerance and dependence. The recent cloning of numerous GABAA receptor subunits opens molecular approaches to studies of tolerance and withdrawal, and the models characterized in our prior studies can be readily extended to these methods. Indeed, our preliminary studies indicate striking decreases in mRNA for several GABAa receptor subunits after prolonged benzodiazepine administration. This finding, which has been confirmed by another laboratory, should be extended to other subunits of the GABAa receptor. In addition, other benzodiazepines will be evaluated during chronic administration and after discontinuation, including in situ hybridization techniques to assess anatomic localization and nuclear run off studies to evaluate effects on transcription. Also, antibodies specific for receptor subunits will be used to assess alterations in subunit protein expression, and to correlate these results with mRNA data. The second major area of study involves pharmacologic interventions which have been proposed to limit benzodiazepine tolerance and dependence. The mouse model we have developed is well-suited to assessing dose-tapering, antagonist and anticonvulsant administration, and partial agonist treatment. The proposed studies will provide a broad picture of effects of chronic benzodiazepines at the molecular level, together with evaluation of interventions that have direct relevance to prevention of benzodiazepine withdrawal.

苯二氮卓类药物是最常见的精神药物 药物在美国和国际上。 临床应用这些 药物的耐受性和身体发育受到限制 依赖 此外，有证据表明， 苯二氮卓类药物滥用和依赖可能导致这种滥用。 的 苯二氮卓耐受和依赖的潜在机制仍然存在 不确定 在本提案的前一阶段，我们制定了 小鼠苯二氮卓类药物耐受和戒断模型， 其特征在于在GABAA受体复合物的详细改变， 该模型 简而言之，苯二氮卓激动剂给药是 与行为耐受和受体下调有关; 停药与短暂的行为戒断有关 与受体上调同时发生的综合征。 慢性拮抗剂和 反向激动剂给药也与受体 上调。 长期拮抗剂和反向激动剂给药 也与受体上调有关。 另外我们有 开发了一个体外系统，以评估苯二氮卓类药物对 培养的皮层神经元。 结果一般与所获得的结果平行 in vivo. 目前的建议是这些模式的延伸 在两个主要领域：1。分子生物学方法; 2。 限制耐受性和依赖性的药物干预。 的 最近克隆了许多GABAA受体亚单位， 容忍和退缩的研究方法和模型 在我们以前的研究中所描述的特征可以很容易地扩展到这些 方法. 事实上，我们的初步研究表明， 苯二氮卓类药物长期给药后几种GABA α受体亚单位的mRNA表达 局 这一发现已被另一个 实验室，应扩展到其他亚基的GABA α受体。 此外，其他苯二氮卓类药物也将在慢性 给药和停药后，包括原位 杂交技术用于评估解剖定位和核运行 以评估对转录的影响。 同时，抗体 将使用对受体亚基特异的抗体来评估 亚基蛋白表达，并将这些结果与mRNA 数据 研究的第二个主要领域涉及药理学 已提出的限制苯二氮卓类药物耐受性的干预措施 和依赖。 我们开发的小鼠模型非常适合 评估剂量递减、拮抗剂和抗惊厥药给药， 和部分激动剂治疗。 拟议的研究将提供一个 慢性苯二氮卓类药物在分子水平上的作用 同时，对具有直接影响的干预措施进行评价， 与预防苯二氮卓类药物戒断的相关性。