Discriminative Effects of Benzodiazepine Withdrawal

描述（由申请人提供）：苯二氮卓类药物在治疗焦虑、失眠和乙醇戒断等疾病方面极为重要。不幸的是，这些药物有滥用和依赖的倾向。正在研究其他药物，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;一种可能的替代品是神经活性类固醇，在许多情况下，其效果与苯二氮卓类药物相同。该实验室最近的研究表明，神经活性类固醇在苯二氮卓类药物依赖性猴中的作用可能会导致对GABAA受体功能如何随苯二氮卓类药物依赖性而变化的新见解，并可能为治疗苯二氮卓类药物戒断提供更好的策略。本申请中的研究旨在进一步探索神经活性类固醇的行为效应，发现神经活性类固醇和苯二氮卓类药物效应之间差异的性质，研究苯二氮卓类药物依赖性的GABAA受体功能变化，并确定这些差异是否可用于临床获益。目的1下的研究评估了神经活性类固醇逆转（目的1A）或预防（目的1B）恒河猴中苯二氮卓类戒断的辨别性、生理性和直接可观察体征的能力。神经活性类固醇在急性戒断的苯二氮卓类药物依赖猴中的意外有效性和相对效力表明，苯二氮卓类药物依赖并不能类似地改变GABAA受体功能的所有方面。目的2A检验负性和中性调节剂的亲和力不因苯二氮卓类药物依赖而改变的假设。目的2B检验对GABAA受体的功效需求将由于苯二氮卓类药物依赖而增加的假设。最后，由于神经活性类固醇似乎具有多种作用机制，因此利用药物识别的选择性来识别有助于其在猴子中的行为效应的受体。目标3A下的研究建立了神经活性类固醇孕烯醇酮的刺激控制，并表征了药理学选择性。将根据目标3b研究作用于苯二氮卓类位点的药物与神经活性类固醇的组合，以确定GABAA受体在孕烷醇酮的辨别性刺激效应中的作用。总之，这些研究将系统地比较正常和苯二氮卓类依赖猴之间的神经活性类固醇与苯二氮卓类位点配体。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，并可能改善苯二氮卓类药物戒断、焦虑、失眠甚至乙醇戒断的治疗。苯二氮卓类药物戒断会使治疗难以中止，是使用这些安全药物的主要限制。该补助金调查其他药物（例如，神经活性类固醇），特别关注这些化合物在治疗苯并二氮杂依赖性中的可能优势。

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 The unexpected effectiveness and relative potency of neuroactive steroids in acutely withdrawn benzodiazepine-dependent monkeys suggest that not all aspects of GABAA receptor function are similarly changed by benzodiazepine dependence.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.