Discriminative Effects of Benzodiazepine Withdrawal

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 The unexpected effectiveness and relative potency of neuroactive steroids in acutely withdrawn benzodiazepine-dependent monkeys suggest that not all aspects of GABAA receptor function are similarly changed by benzodiazepine dependence.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