DISCRIMINATIVE EFFECTS OF BENZODIAZEPINE WITHDRAWAL

苯二氮卓类药物具有良好的身体依赖性。 已经确立并将继续是这一现象的一个重要的不良影响 治疗学的课程。因为苯二氮类药物和相关化合物 继续在医学上广泛使用，有相当大的需求 用于临床前评估药物的依赖性和滥用潜力 这些化合物。当前的应用程序建议研究 苯二氮类药物依赖与药物依赖的辨别刺激效应 每日服用氯氮卓酮(CDP)的恒河猴戒断反应 同时在食物展示的多个时间表下响应 刺激-休克终止(SST)与IM. 注射赋形剂和苯二氮卓类拮抗剂氟马西尼。这个 拟议研究的主要目标是开发一种药物 非人灵长类对苯二氮类药物依赖的判别模型 以及使用此程序评估有关受体的基本问题 苯二氮卓类药物及其相关化合物的调理和功效。之后 在CDP中，氟马西尼和车辆之间建立了刺激控制。 经过治疗的猴子，受试者将被分为两组，每组四只： 其中一组将被用来研究性别差异刺激效应 终止CDP治疗(例如，停药)以及 逆转CDP终止时观察到的任何影响的化合物 治疗；第二组将用于详细描述 氟马西尼等化合物对小鼠的辨别性刺激作用 用CDP治疗的猴子。在这两组中，化合物将被评估为 不仅是因为它们单独使用时的行为影响，而且在 两种化合物一起给药的研究；后者 研究将解决与毒品行动性质有关的问题， 受体(例如，相互作用是简单的、竞争性的拮抗吗？) 以及不同化合物之间的疗效差异。在协作环境中 与T.Cicero博士合作的项目，内分泌功能也将得到监测 在每天接受CDP治疗的恒河猴和猴子身上 经历禁欲或拮抗剂诱导的急性发作 戒烟。第三组四只猴子将被训练成 在符合以下条件的情况下区分氟马西尼和车辆 与使用CDP治疗的猴子的条件相同， 尽管这一群体不会长期接受药物治疗。一秒钟 而拟议研究的较小部分涉及利用 环磷酰胺类药物对猴体内氟马西尼的辨别作用 评价分析，由药物问题学院主办 并作为更大的协作努力的一部分，旨在 表征苯二氮类药物的依赖性和滥用潜力 与药理相关的化合物。这些研究将发展 第一个苯二氮卓类依赖的非人类灵长类动物模型 利用毒品歧视程序，因此将作为 药理桥梁，提供有关的基本信息 抗焦虑药物的作用机制。

The physical dependence potential of benzodiazepines is well established and continues to be an important undesirable effect of this class of therapeutics. Because benzodiazepines and related compounds continue to be used widely in medicine, there is a considerable need for preclinical evaluation of the dependence and abuse potential of these compounds. The current application proposes to study the discriminative stimulus effects of benzodiazepine dependence and withdrawal in rhesus monkeys treated daily with chlordiazepoxide (CDP) while responding under a multiple schedule of food presentation and stimulus-shock termination (SST) and discriminating between i.m. injections of vehicle and the benzodiazepine antagonist flumazenil. The primary goal of the proposed studies is to develop a drug discrimination model of benzodiazepine dependence in non-human primates and the use this procedure to evaluate basic issues regarding receptor mediation and efficacy of benzodiazepines and related compounds. After stimulus control is established between flumazenil and vehicle in CDP- treated monkeys, the subjects will be divided in to two groups of four: one group will be used to study the discriminative stimulus effects of terminating CDP treatment (e.g., withdrawal) as well as the ability of compounds to reverse any effects observed upon termination of CDP treatment; a second group will be used to characterize in detail the discriminative stimulus effects of flumazenil and other compounds in CDP-treated monkeys. In both groups, compounds will be assessed not only for their behavioral effects when administered alone, but also in studies where two compounds are administered together; the latter studies will address issues regarding the nature of drug action at receptors (e.g., is the interaction simple, competitive antagonism?) as well as differences in efficacy among compounds. In a collaborative project with Dr. T. Cicero, endocrine function will also be monitored in rhesus monkeys that are receiving CDP daily and in monkeys undergoing acute episodes of abstinence- or antagonist-induced withdrawal. A third group of four monkeys will be trained to discriminate between flumazenil and vehicle under conditions that are identical to conditions that are used in the CDP-treated monkeys, although this group will not be treated chronically with drug. A second and smaller component of the proposed studies involves utilization of the flumazenil discrimination in CDP-treated monkeys as a drug evaluation assay, under the auspices of the College on Problems of Drug Dependence and as part of a larger collaborative effort designed to characterize the dependence and abuse potential of benzodiazepines and pharmacologically-related compounds. These studies will develop the first non-human primate model of benzodiazepine dependence that utilizes drug discrimination procedures and, thereby, will serve as a pharmacological bridge to provide fundamental information on the mechanism of action of anxiolytics.