Benzodiazepines (BZs) are prescribed widely as anxiolytics, hypnotics, muscle relaxants, and anticonvulsants. Although BZs are considered to be among the safest prescription drugs in modem medicine, their utility is constrained by a number of side effects, including unwanted sedation, impaired motor performance, and the liability for abuse and dependence. The overall goal of this application is to investigate the contribution of different GABAA receptor subtypes to the anxiolytic, abuse-related, and sedative/motoric effects of BZ ligands in relevant nonhuman primate models. Ligands that exhibit preferential binding or preferential agonist activity at GABAA receptors containing different (x subunits will be used to investigate the potential contribution of these receptor subtypes to various behavioral effects of BZs. Behavior predictive of anxiolytic activity will be studied in rhesus monkeys using a conflict procedure in which food-maintained behavior is concurrently suppressed by response-produced presentations of an aversive stimulus. Abuse potential will be studied using a progressive-ratio schedule of IV drug self-administration. Sedation and motor performance will be examined using direct observation techniques and an automated procedure for assessment of motor coordination. Quantitative pharmacological analysis will be used in conjunction with drug interaction studies to investigate the potential contribution of GABAA receptor subtypes across these different behaviors. The results of these studies will provide relevant information for understanding the role of different GABAA receptor subtypes in the anxiolytic, abuse-related, and sedative/motoric effects of BZ ligands. The results also should facilitate identification of effective anxiolytic compounds with decreased side effects and reduced abuse potential.
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