Discriminative Effects of Benzodiazepine Withdrawal

苯二氮卓戒断的区别效应

基本信息

批准号：
7568922
负责人：
LISA R GERAK
金额：
$ 33.33万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-03-15 至 2012-11-30
项目状态：
已结题

项目摘要

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 The unexpected effectiveness and relative potency of neuroactive steroids in acutely withdrawn benzodiazepine-dependent monkeys suggest that not all aspects of GABAA receptor function are similarly changed by benzodiazepine dependence.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

描述（由申请人提供）：苯二氮卓类药物在治疗诸如焦虑，失眠和乙醇戒断等疾病方面非常重要。不幸的是，这些药物具有滥用和依赖责任。正在研究其他药物，以提供类似于苯二氮卓类似虐待或依赖责任的治疗作用；一种可能的替代是神经活性类固醇，其作用在许多条件下与苯二氮卓类药物质量相同。该实验室的最新研究表明，神经活性类固醇在苯二氮卓类依赖性猴子中的影响可能会导致对GABAA受体功能如何随苯二氮卓类依赖性变化的新见解，并可以提供更好的策略来治疗苯二氮二氮的戒断。该应用中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之间差异的性质，研究与苯二氮卓类药物依赖性的GABAA受体功能的变化，并确定这些差异是否可以利用这些差异来利用临床益处。 AIM 1下的研究评估神经活性类固醇反向（AIM 1A）或预防（AIM 1B）在恒河猴中苯并二氮卓类药物的歧视性，生理和可观察到的迹象。神经活性类固醇在急性撤回的苯二氮卓类依赖性猴子中的意外有效性和相对效力表明，GABAA受体功能的所有方面并非所有方面都因苯二氮卓类药物的依赖性而发生了类似的改变。 AIM 2A检验了以下假设：苯二氮卓类依赖性的影响和中性调节剂的亲和力不会改变。 AIM 2B检验了以下假设：苯二氮卓类依赖性，对GABAA受体的疗效需求将增加。最后，由于神经活性类固醇似乎具有多种作用机理，因此利用药物歧视的选择性来识别有助于其在猴子行为影响的受体。 AIM 3A下的研究通过神经活性类固醇妊娠酮建立刺激控制，并表征了药理学选择性。将研究在AIM 3B下与神经活性类固醇结合使用在苯二氮卓网站上作用的药物，以确定GABAA受体在妊娠的歧视性刺激作用中的作用。综上所述，这些研究将系统地将神经活性类固醇与正常和苯二氮卓类依赖性猴子之间的苯二氮卓位点配体进行比较。这些研究将提高我们对GABAA受体功能如何随苯二氮卓类药物依赖性而变化的理解，将提高我们对神经活性类固醇药理的理解，并可能导致改善苯二氮卓类药物戒断，焦虑，失眠症，甚至甚至乙醇的治疗方法。苯二氮卓类药物的戒断可能会使对治疗的中断，这是使用这些其他安全的药物的主要限制。该赠款研究了其他药物（例如神经活性类固醇），特别注意这些化合物在治疗苯二氮卓依赖性方面的可能优势。