The overall objective of the proposed research is to characterize the effects, on complex behavioral processes, of different benzodiazepines which are used therapeutically and are subject to both acute and chronic abuse. Despite the dependence-producing potential of the benzodiazepines and the distinct behavioral effects associated with their acute and chronic use in man, there has been no systematic investigation or comparison of their effects on complex behavioral processes such as learning and memory. Complex operant tasks involving both the acqusition and performance of discriminations in nonhuman primates and rats will be the major focus of investigation. In monkeys, a multiple schedule will be used in order to make a direct comparison of the effects of various benzodiazepines on the acquisition and performance of conditional discriminations. Similarly, a multiple schedule of stimulus-duration and fixed-ratio discriminations will be used in order to directly compare the effects of these same drugs on temporal and response-based discriminations. Parallel studies will be conducted in rats. In the first series of experiments, the acute effects of """"""""long: (diazepam, flurazepam), """"""""intermediate"""""""" (lorazepam, oxazepam), and """"""""short"""""""" (midazolam, triazolam) acting benzodiazepines on learning and performance will be determined. As a comparison, the acute effects of pentabarbital and phenobarbital will also be examined. In related studies it will be determined whether the effects of the benzodiazepines on accuracy and rate of responding exhibit stereospecificity. In a second series of experiments the acute effects of various doses of diazepam, oxazepam, triazolam and pentobarbital will each be tested in combination with various doses of the specific benzodiazepine antagonist RO15-1788. The purpose of these studies is to determine the extent to which the effects of these drugs on accuracy and rate of responding are mediated by a specific mechanism of action. Finally, the chronic effects of diazepam and lorazepam will be investigated. The purpose of these studies is to characterize both the chronic (eg., behavioral tolerance) and postchronic (eg., behavioral dependence) effects of these drugs on complex behavioral processes. Together, these studies will generate a significant amount of new information concerning how both the acute and chronic administration of various benzodiazepine may affect the learning and performance of complex behavioral tasks.
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