Recreational abuse of newly emerging """"""""club drugs"""""""" including atypical hallucinogens is a significant and growing national problem. Abuse of these drugs among adolescents, often exacerbated by internet websites, is a particular concern. Research in this project will focus on four such compounds for which there are major gaps in our understanding of the comparative human clinical pharmacology: GHB (gamma- hydroxybutyric acid), ketamine, dextromethorphan, and salvinorin A. For all four compounds, double-blind dose-effect studies will be conducted in subjects with histories of drug abuse and drug effects will be assessed using various subjective, behavioral, psychomotor performance, cognitive, memory and/or physiological measures. More specifically, Experiments 1 and 2 will extend previous studies of GHB, a novel abused sedative, to provide new information about the reinforcing and behavioral/cognitive effects of GHB as usually abused by studying the repeated self-administration of low doses of GHB over 3-hour self- administration sessions, and by comparing the effects of GHB to ethanol, the world's most commonly abused sedative drug. Experiments 3-5 will advance understanding of the abuse liability and high dose effects of three compounds abused for their dissociative and hallucinogenic effects. In all three experiments, a dose run-up pilot study will precede the subsequent randomized cross-over comparative pharmacology study comparing placebo and three doses each of the compound of interest relative to a comparison standard. More specifically, Experiment 3 will characterize the effects of ketamine, a classic NMDA (N- methyl-D-aspartic acid) antagonist, by evaluating a range of intramuscularly administered doses of ketamine relative to intramuscularly administered midazolam as the comparison standard. Experiment 4 will examine a range of orally administered doses of the dextromethorphan, a widely available novel NMDA antagonist, relative to oral doses of ketamine as the comparison standard. Finally Experiment 5 will use a similar approach to characterize the effects of salvinorin A, a novel selective kappa opioid agonist that is becoming a significant hallucinogen of abuse. These studies will provide new information about the abuse potential and toxic effects of four recreationally abused drugs of national concern. Because the drugs proposed for study have unique and selective cellular sites of action (i.e. GHB/GABAB, NMDA, and kappa opioid receptors), this research also may provide new insights about basic pharmacological mechanisms of action, with relevance for developing new therapies for a variety of disorders including drug dependence. Ultimately, this comparative pharmacology research program should have relevance to the development of drug abuse prevention and treatment strategies for these emerging drugs of abuse. ? ? ?
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