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ANALYSIS OF BENZODIAZEPINE DEPENDENCE

苯二氮卓依赖性分析

基本信息

批准号：
3208604
负责人：
RICHARD M EISENBERG
金额：
$ 8.08万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-04-01 至 1990-03-31
项目状态：
已结题

项目摘要

There is substantial evidence in clinical therapy that psychic dependence occurs to the benzodiazepine tranquilizers as it does to other sedative/hypnotics. The problem of physical dependence has been more difficult to demonstrate. Often, in the clinical setting the spontaneous withdrawal associated with the cessation of therapy is confused with the original symptoms for which anxiolytic medication was first prescribed. With the availability of specific benzodiazepine antagonists, drug-precipitated withdrawal has been reported. Our objective is to examine several aspects of benzodiazepine dependence--pharmacological, anatomical and physiological. A model system which shows dependence in rats to this class of drugs is described. Dependence is induced by pretreating with diazepam HC1 (5 mg/kg, IP) for 8 days. Approximately 3 hours after the final dosing, either of the benzodiazepine antagonists, CGS-8216 or Ro 15-1788, is given to precipitate a withdrawal response as demonstrated by a significant increase in plasma corticosterone. This model will be substantiated by correlating changes in hormone response with behavioral activity. The use of plasma corticosterone to indicate the stress of withdrawal is made possible through the use of enclosed experimental chambers and appropriate surgical procedures. Blood samples are obtained and injections made through a chronic indwelling catheter inserted via the external jugular vein to the entrance of the right atrium. With the stereotaxic implantation of intracerebroventricular cannula guides, injections or pellet implants will be made into the cerebrospinal fluid or tissue sites in the hippocampus to examine benzodiazepine dependence and withdrawal precipitation. Further, electrolytic and neurocytotoxic lesion studies are proposed to confirm the involvement of specific neurotransmitters and anatomical sites in this process. These experiments will be amplified with evaluations of the neurotransmitter profile: serotonin, GABA, norepinephrine, dopamine, and acetylcholine in various areas of the brain as well as an autoradiographic analysis of benzodiazepine receptor density and affinity. It is anticipated that the results of these experiments will lend greater insight into the process of benzodiazepine dependence, the mechanisms and processes involved, and the influence of specific sites and neurotransmitters in the central nervous system.

在临床治疗中有大量证据表明精神依赖对苯二氮卓类镇静剂的影响与对其他镇静剂/催眠药。身体依赖的问题很难证明。通常，在临床环境中，自发的与停止治疗相关的戒断与最初开了抗焦虑药物的最初症状。随着特定苯二氮卓类拮抗剂的问世，据报道，有药物导致的戒断。我们的目标是检查苯二氮类药物依赖的几个方面--药理学，解剖学和生理学上的。显示依赖关系的模型系统老鼠对这类药物进行了描述。依赖是由以下因素引起的静脉注射地西潘(5 mg/kg，ip)8d。大约3 在最后一次给药数小时后，苯二氮卓类拮抗剂中的任何一种， CGS-8216或RO15-1788，用于催促退出反应，如下所示表现为血浆皮质酮显著增加。这模型将通过将激素反应的变化与行为活动。用血浆皮质酮来提示撤退的重音是通过使用封闭的实验室和适当的外科手术。血液样本通过慢性留置导管获得和注射经颈外静脉插入右侧入口处中庭。脑室内立体定位术插管引导、注射或颗粒植入将被制成检查海马区的脑脊液或组织部位苯二氮类药物依赖与戒断沉淀。此外，建议进行电解性和神经细胞毒性损伤研究以证实特定神经递质和解剖部位在这一过程中的参与进程。这些实验将通过评估神经递质谱：5-羟色胺、GABA、去甲肾上腺素、多巴胺和大脑不同区域的乙酰胆碱以及放射自显影苯二氮卓类受体密度和亲和力的分析。它是预计这些实验的结果将提供更多的洞察力探讨苯二氮类药物依赖的过程、机制和过程以及特定部位和神经递质在脑内的影响中枢神经系统。