The behavioral effects of abused drugs have been shown to depend on the organism's prior behavioral experience, as well as on the more immediate characteristics of behavior and its controlling environment. Experiments outlined in this proposal are designed to use these behavioral principles together with selected pharmacological agents to examine and clarify the behavioral and pharmacological mechanisms underlying the actions of the benzodiazepines. Performances of squirrel monkeys will be established and maintained under procedures in which responding produces either food or electric shock presentation. Previous research has shown that benzodiazepines differentially affect these behaviors by increasing food-maintained responding and either decreasing or eliminating comparable responding maintained by electric shock. Punished and unpunished performances, also differentially sensitive to the benzodiazepines, will also be employed. Dose-response functions for selected benzodiazepines, nonbenzodiazepine sedative-hypnotics such as the barbiturates, and novel, clinically-effective compounds such as buspirone, will be obtained when administered alone and in the presence of other agents. Of particular interest are the recent benzodiazepine receptor antagonists, as well as compounds such as the Beta-carbolines and purinergic drugs which have been shown to either antagonize the effects of the benzodiazepines or interact with the benzodiazepine receptor in as yet incompletely understood ways. Further studies will examine how the behavioral effects of the benzodiazepines are modified by other compounds with relatively specific activity on certain neurotransmitter systems. These include compounds which are agonists and antagonists of the gammaaminobutyric acid, serotonin and noradrenergic systems. These studies will then be extended to conditions where the behavioral effects of the benzodiazepines are reversed by providing a suitable behavioral history. These experiments should provide valuable information at the integrative level of behavior on the behavioral and pharmacological mechanisms underlying the activity of a major class of abused drugs.
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