A series of experiments is proposed to investigate the comparative behavioral pharmacology and abuse liability of novel sedative drugs, including prescription sedative-hypnotics and the currently abused """"""""club drugs"""""""" GHB and ketamine which are considered to represent a significant public health problem. Drugs will be administered under double-blind conditions in capsules, oral solutions, or intramuscular injections. The effects of drug administration will be assessed using various subjective, psychomotor performance, cognitive, memory and physiological measures. Experiments 1-6 will provide detailed dose-effect, time-course, and relative potency data. A series of three dose-effect experiments will assess subjective effects, performance impairment, and abused liability of a range of doses (including high doses) of several novel abused sedative drugs in volunteers with histories of drug abuse who will reside on a residential research laboratory: GHB vs. triazolam (Exp. 1); ketamine vs. midazolam (Exp. 2); and clonidine vs. alprazolam (Exp. 3). Three-dose-effect experiments in normal subjects will focus on evaluation of subtle cognitive and memory effects at relatively low doses: GHB vs. triazolam (Exp. 4); ketamine vs. midazolam (Exp. 5); and zaleplon vs. triazolam (Exp. 6). Exp 7 will examine the interaction of GHB with ethanol and compare this to the interaction of triazolam with ethanol. The final two experiments will extend work on comparative pharmacology by using drug discrimination procedures to differentiate between GHB and triazolam (Exp 8) and between zolpidem and triazolam (Exp. 9). Because the novel drugs proposed for study have unique cellular sites of action, this research may provide new insights about basic behavioral and pharmacological mechanisms of action. These studies will also have implications for recreational abuse of sedatives as well as the toxic consequence of such use. This comparative pharmacology research program, with its particular focus on sedatives, may ultimately contribute to an understanding of a biological basis of sedation and sleep, and should contribute to efforts to develop and identify new classes of sedative hypnotic compounds which have reduced potential for performance and cognitive impairment and abuse.
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