Research is proposed in subjects with histories of drug abuse and in normal subjects to investigate performance impairments, subjective effects and reinforcing effects of anxiolytic-sedative drugs. One series of experiments will assess the effects of anxiolytic-sedative drugs in volunteers with histories of sedative drug abuse who will reside on an inpatient research ward. These studies will provide detailed dose-effect, time-course and relative potency data across a wide range of measures. Subjective scales and behavioral choice comparisons will also provide information about differences in reinforcing effects. Specifically, four experiments will compare the effects of a range of doses of lorazepam with a range of doses of methyprylon, midazolam, flunitrazepam and several novel anxiolytics. Four additional experiments will extend previous dose-effect studies with pentobarbital, diphenhydramine, methocarbamol and buspirone by examining the relationship between subjective measures of abuse liability (e.g. rating of liking) and drug choice (relative to placebo and lorazepam) and, furthermore, will examine how repeated exposure to the drug conditions affect ratings of liking and choice. A concurrent series of nonresidential experiments will examine the discriminative and reinforcing effects of low and moderate doses of benzodiazepines. One set of studies will be conducted in subjects without histories of drug abuse to examine discriminative effects of benzodiazepines. These studies will determine thresholds for discriminative sensitivity, examine pharmacological specificity, and cross-generalization with buspirone, characterize the effects of chronic benzodiazepine administration (tolerance) on discrimination, and determine the effects of discrimination training on the reinforcing and other effects of benzodiazepines. A final set of studies will manipulate benzodiazepine dose and degree of task difficulty to extend previous research showing that benzodiazepine reinforcement can be modulated by background behavioral contingencies. There is concern about the misuse and abuse of benzodiazepine anxiolytic-sedative drugs, which are widely prescribed psychotropic medications. Recent research developments in benzodiazepine pharmacology raise the possibility of dissociating the abuse and dependence activity of these drugs from 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 should contribute to efforts to develop new classes of anxiolytic-sedative compounds which have reduced potential for performance impairment and abuse. More generally, the data will contribute to an understanding of anziolytic-sedative drug abuse and will ultimately contribute to development of improved prevention, control and treatment procedures.
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