Benzodiazepines have remained the most commonly prescribed drugs for the treatment of caronic anxiety and insomnia since the 1960s. Chronic use of benzodiazepines is often associated with the development of physical dependence and addiction, particularly in populations with a history of drug or alcohol abuse. Concern regarding the public health consequences of benzodiazepine-related physical dependence and abuse liability has led to the recent development of novel benzodiazopine-like agonists with low intrinsic activity or with receptor-subtype selectivity. Yet, the complete pharmacological and behavioral characterization of these novel compounds is in its early stages. To meet the need for improved preclinical methods with which to study the dependence and abuse liability of these and fututre novel benzodiazpines, studies are proposed to evaluate the roles of agonist efficacy and selectivity in the development of tolerance to and dependence on benzodiazepine-like drugs. First, the acute agonist, antagonist, or partial agonist effects of different benzodiazepine-like drugs in monkeys will be quantitatively assessed using three established experimental procedures. Results of these experiments will be used to functionally categorize these drugs on the basis of efficacy and subtype selectivity. They also will provide an empirical foundation for subsequent studies. Second, the roles of efficacy and selectivity in the development of tolerance and dependence to benzodiazopine-like drugs will be studied in monkeys that are chronically exposed to full, partial or selective agonists. Full dose-effect functions for drugs differing in efficacy or selectivity will be determined during the different chronic treatments to provide information on how their behavioral effects arc thereby modified. The behavioral effects of nonbenzodiazepine GABAA modulators also will be examined to evaluate other changes in GABAA function that may result f om chronic benzodiazepine administration. The results of chronic studies will permit a quantitative analysis of the relationship between functional efficacy or receptor-subtype selectivity and the magnitude of tolerance and dependence that develops to benzodiazepine-like drugs. Overall, the proposed research will yield knowledge essential to understanding determinants of drug dependence in primates and predicting the addiction liability of novel benzodiazopine drugs.
