Research is proposed in subjects with histories of drug abuse and in normal subjects to characterize the pharmacological profiles and abuse liability of novel benzodiazepine and nonbenzodiazepine sedative-anxiolytics. One series of experiments will assess the effects of sedative-anxiolytic drugs in volunteers with histories of sedative drug abuse who will reside on a residential research laboratory. These studies will provide detailed dose-effect, time-course and relative potency data across a wide range of measures of behavioral, subjective and reinforcing effects. Specifically, these experiments will compare the effects of a range of doses of triazolam or alprazolam with flunitrazepam, clonidine, phencyclidine, methyprylon. A concurrent series of nonresidential experiments will extend previous research examining the reinforcing, discriminative stimulus, and antagonist-precipitated withdrawal effects of benzodiazepines in subjects without histories of drug abuse. One series of studies will examine reinforcing effects in normal subjects by investigating differences in the reinforcing effects of different benzodiazepine receptor agonists in moderate drinkers, and by studying reinforcing effects in individuals with sleeping problems and anxiety. Another set of studies will manipulate dose and degree of task difficulty to extend previous research showing that benzodiazepine reinforcement can be modulated by the behavioral requirements following drug ingestion. One study will use drug discrimination methods to differentiate among drugs by training a triazolam vs. zolpidem vs. placebo discrimination and then testing a series of benzodiazepine receptor agonists. A final set of studies will characterize antagonist-precipitated withdrawal after intravenous and oral administration of flumazenil to subjects with histories of long-term exposure to therapeutic doses of benzodiazepines. There is concern about benzodiazepine abuse and physical dependence among polydrug abusers and patients. Recent research developments in benzodiazepine pharmacology raise the possibility of dissociating the abuse and dependence activity of these drugs from the various other behavioral and therapeutic actions. This research will provide information about behavioral and pharmacological mechanisms of action and relative abuse liability of these compounds. This research should contribute to efforts to develop new classes of sedative-anxiolytic compounds which have reduced potential for abuse by drug abusers as well as reduced potential for inappropriate chronic use among patients.
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