The revised application is entitled """"""""Human Cocaine Discrimination: Pharmacological Specificity"""""""". The title was changed since less emphasis is given to elucidating the neuropharmacological mechanisms underlying the discriminative stimulus effects of cocaine in human research volunteers. The revised application consists of 5 inpatient, laboratory experiments aimed at characterizing the discriminative stimulus effects of cocaine in humans. Exp. 1 will replicate the only other study that established cocaine as a discriminative stimulus in humans, and extend these findings by testing the discriminative stimulus effects of d- amphetamine and pentobarbital to further determine the pharmacological specificity of the cocaine-placebo discrimination. Exp. 2 will determine the effects of training dose on subsequent discrimination performance. Exp. 3-5 will test the discriminative stimulus effects of 6 compounds (i.e., mazindol, methylphenidate, bupropion, diethylpropion, desipramine and fluoxetine) in cocaine-trained humans. d-Amphetamine and pentobarbital will be included as a positive and negative control, respectively, in each of these experiments. Two training conditions will be used in each experiment to further explore the influence of cocaine training dose on subsequent discrimination performance. Drug-effect and mood questionnaires will be used in each experiment. The experiments proposed in this application have at least 6 important implications. First, these experiments will lay the groundwork for studying the discriminative stimulus effects of cocaine in humans. Second, these experiments will determine the influence of cocaine training dose on subsequent drug discrimination performance. Third, because some of the compounds to be tested exert their effects primarily via dopamine systems (i.e., mazindol, methylphenidate, bupropion, diethylpropion) and others via norepinephrine (i.e., desipramine) or serotonin (i.e., fluoxetine) systems, these experiments will begin to elucidate the neuropharmacological mechanisms underlying the discriminative stimulus effects of cocaine in humans, and whether these mechanisms vary across different training conditions. Fourth, because all of the compounds have previously been tested in nonhuman laboratory animals trained to discriminate between cocaine and vehicle, these experiments will begin to determine, albeit indirectly, to what extent the findings from preclinical studies generalize to humans. Fifth, the inclusion of drug-effect and mood questionnaires will provide ancillary information concerning the relationship between the discriminative stimulus and subjective effects of cocaine. Finally, because the interoceptive and discriminative stimulus effects of cocaine clearly contribute to its abuse, the experiments proposed in this application could provide information relevant to the treatment of cocaine abuse.
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