It is well known that tolerance and physical dependence develop after repeated exposure to benzodiazepines (BDZs). Despite the many studies on tolerance to BDZ effects, very little has been done to compare tolerance among the various BDZs. With the advent of BDZs that are preferentially anxiolytic (with little or no sedation), such studies can provide information on the mechanism(s) of action by which the BDZs produce their varied effects. For example, it might be inferred that BDZs which exhibit cross-tolerance with each other share a similar mechanism of action whereas compounds that do not show cross-tolerance produce their effects through different mechanisms. In this proposal, schedule-controlled responding will be used to examine tolerance to the effects of the prototypic sedative-anxiolytic BDZ, chlordiazepoxide, and to the newer non-sedative anxiolytic BDZ, tetrazepam. Experiments will then be conducted to determine whether tolerance to chlordiazepoxide or tetrazepam confers cross-tolerance to other sedative-anxiolytic BDZs as well as to non-sedative anxiolytics. Schedule-controlled responding was chosen as the dependent variable in examining BDZ tolerance and dependence because it provides stable, yet sensitive, baselines for studying drug effects on behavior over long periods of time. In addition, previous studies indicate that tolerance to BDZs does develop under schedules of food presentation. A second series of experiments will be conducted to determine whether animals that have developed tolerance to chlordiazepoxide and/or tetraepam are also dependent on these drugs, as evidenced by the occurrence of withdrawal, either spontaneous (when chronic BDZ is terminated) or precipitated by administration of the BDZ antagonist Ro 15-1788. In addition, because BDZs are also known to produce a withdrawal syndrome following acute BDZ administration dependence), a third series of experiments will be conducted to determine whether there is disruption of schedule-controlled behavior following acute (single dose) BDZ administration, thus providing us with a sensitive indicator of acute dependence. In future experiments the acute dependence model might be used to examine the contribution of various neurotransmitters to the development of tolerance and dependence, to characterize drugs used in the treatment of withdrawal and to assess the ability of novel drugs to produce dependence.
