CHRONIC BENZODIAZEPINES: BEHAVIOR AND NEUROCHEMISTRY

慢性苯二氮卓类药物：行为和神经化学

• 批准号: 6495269
• 负责人: DAVID J GREENBLATT
• 金额: $ 4.38万
• 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 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6495269
• 关键词: GABA receptor; age difference; autoradiography; benzodiazepine receptor; benzodiazepines; drug addiction; drug adverse effect; drug tolerance; drug withdrawal; excitatory aminoacid; glutamate receptor; histochemistry /cytochemistry; in situ hybridization; laboratory mouse; neurochemistry; northern blottings; polymerase chain reaction; protein kinase C; psychopharmacology; receptor binding; receptor expression; second messengers; stimulant /agonist; substance abuse related behavior; western blottings

DESCRIPTION: Benzodiazepine agonists continue to be the principal pharmacologic option available for the treatment of anxiety, panic disorders, and insomnia. Despite an overall record of efficacy and safety that is generally favorable, concerns regarding tolerance, dependence, withdrawal syndromes, and abuse of benzodiazepines remain issues of medical and public health importance. Also of concern is the usage of these agents by the elderly, who may have increased susceptibility to adverse CNS depressant effects. There is continuing need for basic mechanistic data on the causes and consequences of tolerance and withdrawal; such data can form the basis for strategies to identify patients at highest risk, or to develop other pharmacologic interventions to minimize the risk of tolerance and dependence. We propose to continue and broaden our ongoing research program having this overall objective. The core of the model involves male CD-1 mice that receive continuous infusions of benzodiazepine agonists, or vehicle control, for up to 14 days via implanted osmotic pumps. During the period of infusion, and in the 7-day post-infusion withdrawal period, the following outcomes are determined: computerized ambulatory activity; pentylenetetrazole seizure threshold; in vivo benzodiazepine receptor occupancy; in vitro receptor binding; GABA(A) receptor function; receptor autoradiography; receptor subunit mRNA expression; and plasma and brain concentrations of infused substances. The principal research questions to be addressed include the following: a. Do benzodiazepine agonists with relative selectivity for the BZ1 receptor subtype have reduced liability to produce tolerance, dependence and withdrawal? b. Does the protein kinase C second messenger pathway have a modulatory role in benzodiazepine-associated tolerance? c. Does the excitatory amino acid (EAA) receptor system co-modulate the development of tolerance and withdrawal associated with benzodiazepine agonists, and does pharmacologic antagonism of specific EAA receptor systems modify these phenomena? d. Do aging organisms have differential patterns of benzodiazepine tolerance and withdrawal? Are such differences explained by protein kinase C or EAA regulatory systems? These studies should continue to provide mechanistic data relevant to the clinical management and prevention of tolerance and dependence problems associated with therapeutic use of benzodiazepine agonists.

描述：苯二氮卓激动剂仍然是主要的药理学 可用于治疗焦虑症、恐慌症和失眠症。 尽管疗效和安全性的总体记录总体上是有利的， 对药物的耐受性、依赖性、戒断综合征和滥用的关切 苯并二氮杂卓仍然是具有医学和公共卫生重要性的问题。评价很 令人担忧的是，老年人使用这些药物的情况可能有所增加， 对中枢神经系统不良反应的敏感性。继续需要 关于耐受性的原因和后果的基本机械数据， 退出;这些数据可以形成识别患者的策略的基础， 最高风险，或开发其他药物干预措施，以尽量减少 容忍和依赖的风险。我们建议继续并扩大我们的 正在进行的研究计划具有这一总体目标。模型的核心 涉及接受苯二氮卓类药物连续输注的雄性CD-1小鼠， 激动剂或载体对照，通过植入的渗透泵持续长达14天。 输注期间和输注后7天停药期间 期间，确定了以下结果：计算机化门诊 活性;戊四氮发作阈;体内苯二氮受体 占据;体外受体结合; GABA（A）受体功能;受体 放射自显影;受体亚单位mRNA表达;血浆和脑 输注物质的浓度。主要研究问题是 所涉及的问题包括：a.苯二氮卓类激动剂与相对 对BZ 1受体亚型的选择性降低了产生 容忍、依赖和退缩？B.蛋白激酶C是第二个 信使途径在苯二氮卓类药物相关性 宽容？C.兴奋性氨基酸（EAA）受体系统是否参与调节 与苯二氮卓类药物相关的耐受性和戒断的发展 激动剂，以及特定EAA受体系统的药理学拮抗作用 改变这些现象？D.衰老的生物体是否有不同的 苯二氮卓类药物的耐受性和戒断反应这种差异是否可以用 蛋白激酶C或EAA调节系统？这些研究应继续下去， 提供与临床管理和预防相关的机械数据， 耐受性和依赖性问题与治疗使用的 苯二氮卓类激动剂。