CHRONIC BENZODIAZEPINES: BEHAVIOR AND NEUROCHEMISTRY

描述：苯二氮卓类激动剂仍然是主要的药理作用药物。 可用于治疗焦虑症、恐慌症和失眠。 尽管总体疗效和安全性记录总体上是有利的， 对耐受性、依赖性、戒断综合症和滥用 苯二氮卓类药物仍然是医疗和公共卫生的重要问题。也可以是 令人担忧的是老年人使用这些药物的情况，他们可能增加了 对中枢神经系统抑制药不良反应的易感性。有持续的需求 关于容忍的原因和后果的基本机制数据 停药；这些数据可以成为在以下方面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，以将 容忍和依赖的风险。我们建议继续并扩大我们的 有这个总体目标的正在进行的研究计划。该模型的核心是 涉及接受连续输注苯二氮类药物的雄性CD-1小鼠 通过植入的渗透泵，激动剂或车辆控制，最长可持续14天。 在输液期间和输液后7天内停药 在此期间，确定下列结果：计算机化门诊 活性；戊四氮惊厥阈值；体内苯二氮卓受体 占有率；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。主要的研究问题是 涉及的问题包括：a.苯二氮卓类激动剂是否与相关的 对BZ1受体亚型的选择性降低了产生 宽容、依赖和退缩？B.蛋白激酶C是不是第二个 信使通路在苯二氮类药物相关性中的调节作用 宽容？C.兴奋性氨基酸(EAA)受体系统是否共同调节 苯二氮类药物耐受和戒断的研究进展 激动剂，并对特定的EAA受体系统进行药理拮抗 改变这些现象？D.衰老的生物体是否有不同的模式 苯二氮类药物耐受和停药？这种差异是由什么来解释的 蛋白激酶C或EAA调节系统？这些研究应该继续 提供与临床管理和预防有关的机械性数据 与治疗用药有关的耐受性和依赖性问题 苯二氮卓类激动剂。

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.