ANALYSIS OF BENZODIAZEPINE DEPENDENCE

苯二氮卓依赖性分析

• 批准号: 3208601
• 负责人: RICHARD M EISENBERG
• 金额: $ 8.09万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1989-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3208601
• 关键词: autoradiography; behavioral medicine; benzodiazepines; biological models; brain metabolism; corticosterone; diazepam; drug addiction antagonist; drug metabolism; drug withdrawal; electrochemistry; high performance liquid chromatography; hormone regulation /control mechanism; model design /development; neurotransmitter metabolism; plasma; radiotracer; stereotaxic techniques; tissue /cell culture; tranquilizer

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.

临床治疗中有大量证据表明精神依赖 发生在苯二氮卓类镇静剂，因为它对其他 镇静剂/催眠药。 身体依赖的问题已经越来越多 很难证明。 通常，在临床环境中， 与停止治疗相关的戒断与 首次开抗焦虑药物的原始症状。 随着特定苯二氮卓类拮抗剂的可用性， 据报道，药物促戒断。 我们的目标是 检查苯二氮卓类药物依赖的几个方面--药理学， 解剖学和生理学的。 一个模型系统，它显示出依赖性， 描述了大鼠对这类药物的耐受性。 依赖性是由 用盐酸地西泮（5 mg/kg，IP）预处理8天。 约3 在最后一次给药后数小时，苯二氮拮抗剂， 给予CGS-8216或Ro 15-1788以促使戒断反应， 表现为血浆皮质酮显著升高。 这 模型将通过将激素反应的变化与 行为活动 使用血浆皮质酮来指示 通过使用封闭的 实验室和适当的外科手术。 血样 通过长期留置导管进行注射 通过颈外静脉插入右侧入口 中庭 脑室内立体定向植入 将插管导向器、注射剂或颗粒植入物制成 脑脊髓液或海马体中的组织部位进行检查 苯二氮卓类药物依赖和戒断沉淀。 此外，本发明还 电解质和神经细胞毒性损伤研究建议确认 特定的神经递质和解剖部位参与其中， 过程 这些实验将通过对这些实验的评估来扩大。 神经递质谱：血清素、GABA、去甲肾上腺素、多巴胺和 乙酰胆碱在大脑的各个领域，以及放射自显影 苯二氮卓受体密度和亲和力的分析。 是 预计这些实验的结果将提供更深入的了解 苯二氮卓类药物依赖的机制和过程 参与，以及特定网站和神经递质的影响， 中枢神经系统