Discriminative Effects of Benzodiazepine Withdrawal

描述(申请人提供)：苯二氮卓类药物在治疗焦虑症、失眠症和酒精戒断等疾病中非常重要。不幸的是，这些药物有滥用和依赖的责任。其他药物正在研究中，以提供与苯二氮卓类药物类似的治疗效果，减少滥用或依赖倾向；一种可能的替代药物是神经活性类固醇，在许多情况下具有与苯二氮卓类药物相同的效果。该实验室最近的研究表明，神经活性类固醇对苯二氮类药物依赖猴子的影响可能导致对GABAA受体功能随苯二氮类药物依赖而变化的新见解，并可能为治疗苯二氮类药物戒断提供更好的策略。这项应用的研究旨在进一步探索神经活性类固醇的行为影响，发现神经活性类固醇和苯二氮卓类药物的作用差异的本质，调查苯二氮类药物依赖时GABAA受体功能的变化，并确定这些差异是否可以用于临床。目标1下的研究评估了神经活性类固醇逆转(目标1A)或预防(目标1B)苯二氮类药物戒断的辨别性、生理学和直接可观察到的迹象的能力。在急性戒断苯二氮类药物依赖的猴子中，神经活性类固醇的意想不到的有效性和相对效力表明，并不是GABAA受体功能的所有方面都会因苯二氮类药物依赖而发生类似的变化。Aim 2A验证了负性和中性调节剂的亲和力不会因苯二氮依赖而改变的假设。目的2B验证苯二氮类药物依赖会增加对GABAA受体的药效需求的假设。最后，因为神经活性类固醇似乎有多种作用机制，所以利用药物识别的选择性来识别对猴子的行为影响有贡献的受体。AIM 3A项下的研究建立了神经活性类固醇孕酮的刺激控制，并表征了药理选择性。作用于苯二氮卓部位的药物将与目标3b项下的神经活性类固醇结合进行研究，以确定GABAA受体在孕酮的区别性刺激效应中的作用。综上所述，这些研究将系统地比较正常猴子和苯二氮依赖猴子之间的神经活性类固醇和苯二氮卓类配体。这些研究将提高我们对GABAA受体功能如何随着苯二氮卓类药物依赖而变化的理解，将提高我们对神经活性类固醇药理学的理解，并可能导致改进对苯二氮卓类戒断、焦虑、失眠甚至酒精戒断的治疗。停用苯二氮卓类药物会使停止治疗变得困难，也是限制这些原本安全的药物使用的主要因素。这笔赠款调查其他药物(例如，神经活性类固醇)，特别注意这些化合物在治疗苯二氮类药物依赖方面的可能优势。

DESCRIPTION (provided by applicant): Benzodiazepines are extremely important in the treatment of disorders, such as anxiety, insomnia and ethanol withdrawal. Unfortunately, these drugs have abuse and dependence liability. Other drugs are being investigated to provide therapeutic effects similar to benzodiazepines with reduced abuse or dependence liability; one possible replacement is neuroactive steroids, which have effects that are qualitatively the same as benzodiazepines under many conditions. Recent studies from this laboratory indicate that effects of neuroactive steroids in benzodiazepine-dependent monkeys could lead to new insights into how GABAA receptor function changes with benzodiazepine dependence and could provide better strategies for treating benzodiazepine withdrawal. Studies in this application are designed to explore further the behavioral effects of neuroactive steroids, discover the nature of differences between the effects of neuroactive steroids and those of benzodiazepines, investigate changes in GABAA receptor function with benzodiazepine dependence, and determine whether these differences can be exploited for clinical benefit. Studies under Aim 1 assess the ability of neuroactive steroids to reverse (Aim 1A) or prevent (Aim 1B) the discriminative, physiological, and directly observable signs of benzodiazepine withdrawal in rhesus monkeys. The unexpected effectiveness and relative potency of neuroactive steroids in acutely withdrawn benzodiazepine-dependent monkeys suggest that not all aspects of GABAA receptor function are similarly changed by benzodiazepine dependence. Aim 2A tests the hypothesis that affinity of negative and neutral modulators does not change as a consequence of benzodiazepine dependence. Aim 2B tests the hypothesis that efficacy demands at GABAA receptors will increase as a consequence of benzodiazepine dependence. Finally, because neuroactive steroids appear to have multiple mechanisms of action, the selectivity of drug discrimination is exploited to identify receptors that contribute to their behavioral effects in monkeys. Studies under Aim 3A establish stimulus control with the neuroactive steroid pregnanolone and characterize pharmacological selectivity. Drugs acting at benzodiazepine sites will be studied in combination with neuroactive steroids under Aim 3b in order to determine the role of GABAA receptors in the discriminative stimulus effects of pregnanolone. Taken together, these studies will systematically compare neuroactive steroids to benzodiazepine-site ligands between normal and benzodiazepine-dependent monkeys. These studies will improve our understanding of how GABAA receptor function changes with benzodiazepine dependence, will improve our understanding of the pharmacology of neuroactive steroids, and may lead to improved treatments for benzodiazepine withdrawal, anxiety, insomnia, and perhaps even ethanol withdrawal. Benzodiazepine withdrawal can make discontinuation of treatment difficult and is the predominant limitation to the use of these otherwise safe drugs. This grant investigates other drugs (e.g., neuroactive steroids) with particular attention to the possible advantage of these compounds in treating benzodiazepine dependence.