Discriminative effects of benzodiazepine withdrawal

苯二氮卓类药物及其相关的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使用。这些相同的化合物也被滥用，无论是单独使用还是与其他类别的药物（例如，阿片类药物），而长期服用苯二氮卓类药物可导致临床上显著的身体依赖。GABAA受体复合物是其他滥用药物的作用部位（例如，乙醇）和γ-氨基丁酸能系统一般被认为间接调节其它滥用药物（例如，可卡因）。在过去的10年里，从GABA受体的分子研究中已经学到了很多，但这些知识很少应用于行为生物体的研究，特别是关于GABA神经生物学和药物滥用。在该资助下，已经开发了用于研究恒河猴中GABAA调节剂的区别性刺激作用的程序，并且本申请中提出的研究将使用这些程序来研究药物对GABA能系统的作用不同的神经生物学。目标1 III下的研究将比较GABA能和其他药物预防和逆转苯二氮卓类药物戒断的能力，以及在正常受试者中模拟苯二氮卓类药物的主观（辨别）效应的能力。一项平行研究（目标II）将在每天接受α 1-s3选择性正调节剂唑吡坦治疗的猴中建立氟马西尼的辨别力，以测试这种广泛使用的镇静/催眠药是否产生可与地西泮产生的依赖性区分开的依赖性。将在目标III下研究神经活性类固醇，以观察眼睛是否改变作用于GABAA受体复合物的其他化合物的行为效应。这项研究是建立在积极的初步数据与孕烯醇酮和文献显示，神经活性类固醇解偶联苯二氮卓类受体从GABAA受体复合物在体外。化合物的盲法评价将继续由药物依赖性学院药物评价委员会根据目标IV主持。总的来说，这些研究将为GABAA调节剂和相关药物的药物/受体和药物/药物相互作用的性质提供重要的定量信息。这些数据将促进对多种临床相关化合物的GABA能神经传递和滥用倾向的理解。

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.