Because benzodiazepines (BZ) and other anxiolytics are among the most widely prescribed of all medications, anxiolytic misuse, abuse, physiological dependence, and behavioral sequelae of long-term use are of continuing concern. Recent advances in understanding the structure and function of the BZ/GABA-receptor complex have led to development of novel compounds believed to be more selective as anxiolytics or hypnotics and less likely to lead to abuse and physiological dependence. Drug discrimination (DD) procedures in laboratory animals provide highly selective behavioral measures of CNS activity, which often are characterized as being analogous to information on subjective drug effects in humans, and it has been speculated that, with drugs that are self-administered, the drug's reinforcing and discriminative stimulus effects are coextensive. The DD paradigm is promising in its ability to provide unique insight into the degree of correspondence between a rather specific behavioral effect and that drug's activity in a specific neurotransmitter system. One major objective of the project is to explore systematically the possible interrelationships between the discriminative stimulus and reinforcing effects of drugs. There is some suggestion that certain drug histories can increase the probability of self-administering other psychoactive compounds, and experiments will study drug discrimination in the context of self-administration and the effects of histories of drug discrimination training on subsequent self-administration and vice versa. A second major objective of the project is to study not only the generalization profiles for anxiolytic drugs per se but also as a function of previous and concurrent discrimination training with other drugs. A third major objective is to study the discriminative stimulus effects of anxiolytics before, during, and after chronic BZ administration to address specifically the extent to which post-dependent subjects may be more or less sensitive to drug discriminative-stimulus effects. A fourth major objective is to study the extent to which molecular mechanisms of action of anxiolytics and compounds with specific activity at the gamma-aminobutyric acid (GABA)/BZ-receptor complex correspond to their discriminative stimulus effects. Experiments will explore central mediation of the discriminative stimulus effects of GABA/BZ-receptor ligands and the discriminative stimulus effects of novel putative anxiolytics and other compounds showing relatively specific activity in this receptor complex.
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