DISCRIMINATIVE EFFECTS OF BENZODIAZEPINE WITHDRAWAL

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。苯二氮类药物及其相关的γ-氨基丁酸(GABA)A调节剂因其抗焦虑、催眠和抗惊厥作用而被广泛应用。这些相同的化合物也会被滥用，无论是单独使用还是与其他类别的药物(如阿片类药物)联合使用，长期使用苯二氮卓类药物可能导致临床上严重的身体依赖。GABAA受体复合体是其他滥用药物(如乙醇)的作用部位，一般来说，GABA能系统被认为间接调节其他滥用药物(如可卡因)的效果。在过去的10年里，人们从对GABA受体的分子研究中学到了很多，但很少将这些知识应用于行为生物体的研究，特别是关于GABA神经生物学和物质滥用的研究。根据这项拨款，已经开发了研究GABAA调节剂对恒河猴的歧视性刺激效应的程序，本申请中提出的研究将使用这些程序来研究药物对GABA能系统的不同作用的神经生物学。AIM 1ILL下的研究将比较GABA能和其他药物预防和逆转苯二氮类药物戒断的能力，并在正常受试者中模拟苯二氮类药物的主观(辨别)效应。一项平行研究(AIM II)将在每天接受A1-S3选择性正向调节剂唑吡坦治疗的猴子中建立与氟马西尼的区别，以测试这种广泛开出的镇静剂/催眠药是否会产生依赖，这种依赖可以与安定产生的依赖区分开来。神经活性类固醇将在AIM III下进行研究，看看眼睛是否会改变作用于GABAA受体复合体的其他化合物的行为影响。这项研究建立在孕酮的阳性初步数据和一篇文献的基础上，该文献表明，神经活性类固醇在体外将苯二氮卓受体从GABAA受体复合体上解偶联。药物依赖学院药物评价委员会将继续在AIM IV下对化合物进行盲法评价。总的来说，这些研究将为GABAA调节剂和相关药物提供关于药物/受体性质和药物/药物相互作用的重要量化信息。这些数据将促进对GABA能神经传递和各种临床相关化合物的滥用易感性的理解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Benzodiazepines and related gamma-amino butyric acid (GABA)A modulators are used widely for their anxiolytic, hypnotic and anti- convulsant effects. These same compounds are also abused, both alone and in combination with other classes of drugs (e.g., opioids), and long- term use of benzodiazepines can lead to clinically significant physical dependence. The GABAA receptor complex is the site of action of other drugs of abuse (e.g., ethanol) and GABAergic systems, in general, are thought to indirectly modulate the effects of still other drugs of abuse (e.g., cocaine). Much has been learned over the past 10 years from molecular studies on GABA receptors, yet little of this knowledge has been applied to studies in behaving organisms, particularly with regard to GABA neurobiology and substance abuse. Procedures have been developed under this grant for studying discriminative stimulus effects of GABAA modulators in rhesus monkeys and studies proposed in this application will use those procedures to investigate the neurobiology of drugs that vary in their actions on GABAergic systems. Studies under Aim 1ill will compare GABAergic and other drugs for their ability to prevent and reverse benzodiazepine withdrawal and also to mimic the subjective (discriminative) effects of benzodiazepine in normal subjects. A parallel study (Aim II) will establish a discrimination with flumazenil in monkeys treated daily with the a1-s3lective positive modulator zolpidem to test whether this widely-prescribed sedative/hypnotic produces dependence that can be differentiated from that produced by diazepam.Neuroactive steroids will be studied under Aim III to see whether th eye modify the behavioral effects of other compounds that act at the GABAA receptor complex. This study is founded on positive preliminary data with pregnanolone and a literature showing that neuroactive steroids uncouple benzodiazepine receptors from the GABAA receptor complex in vitro. Blind evaluation of compounds will continue the auspices of the Drug Evaluation Committee of the College on Drug Dependence under Aim IV. Collectively, these studies will provide important quantitative information on the nature of drug/receptor and drug/drug interactions for GABAA modulators and related drugs. These data will promote an understanding of GABAergic neurotransmission and abuse liability for a variety of clinically relevant compounds.