Because benzodianzepines and other anxiolytics are among the most widely prescribed of all medications, anxiolytic misuse, abuse, and physiological dependence has been of increasing concern. Drug discrimination procedures can provide highly selective behavioral measures of CNS activity which may be analogous to human subjective drug effects. This project will use drug discrimination procidures in baboons and rats to provide new information about behavioural and pharmacological mechanisms of anxiolytic drug action. Four sets of studies will be conducted over a three-year period. One set of studies will begin to explore interrelationships between drug discrimination and drug self-administration by investigating in baboons the effects of a history of drug discrimination training on subsequent drug self-administration and the effects of a history of drug self-administration on subsequent drug discrimination. A second set of studies will use drug discrimination procedures to investigate physiological dependence on benzodiazepines by conducting drug generalization tests with a variety of drigs in benzodiazepine-dependent baboons trained to discriminate administration of a benzodiazepine antegonist. A third set of studies will further investigate molecular mechansims of action of anxiolytics by investigating drig generalization and antagonism with a variety of drugs in baboons trained to discriminate administration of a benzodiazepine inverse agonist. The fourth set of studies will explore central sites mediating the discriminative stimulus effects of benzodiazepines in rats. In addition to contributing scientific information about mechanisms of action of anxiolytic drugs, the research conducted in this project will utimately have clinical relevance in the treatment and prevention of anxiolytic drug abuse and physiological dependence.
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