Benzodiazepines (BZs) are widely prescribed for the management of anxiety and sleep disorders, but their clinical usefulness is constrained by a significant potential for abuse and dependence. Considerable research is now focused on elucidating the mechanisms of action underlying the behavioral effects of BZs and related drugs, with the goal of increasing clinical utility and reducing abuse liability. Our proposed research will specifically evaluate the role of BZ receptor selectivity and intrinsic efficacy as determinants of the therapeutic vs. abuse -related effects of this important class of drugs. BZ ligands differing in receptor selectivity and/or agonist efficacy will be used as probes to characterize mechanisms of action in nonhuman primate models predictive of anxiolytic activity, subjective effects, and abuse liability. Anxiolytic activity will be evaluated in rhesus monkeys using conflict procedures in which food-maintained behavior is concurrently suppressed by response produced presentations of an aversive stimulus. Subjective effects will be evaluated in monkeys trained to discriminate the conventional BZ agonist triazolam or the BZ 1-selective agonist zolpidem from vehicle. Abuse potential will be evaluated using fixed- and progressive-ratio schedules of i.v. drug self-administration. Quantitative pharmacological tools including isobolographic analysis and in vivo apparent pA2 analysis will be used in conjunction with drug interaction studies to dissociate effects due to receptor selectivity and agonist efficacy. Identification of compounds that are effective anxiolytics lacking abuse potential in our studies will provide needed information for developing safer and more broadly effective anti-anxiety medications, as well as compounds that may be beneficial in the pharmacological management of BZ dependence.
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