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The long-term objective of the proposed research is to provide information about the neurobiological basis of the euphoric effects of abused drugs in humans. It is generally believed that the discriminative stimulus and subjective effects associated with abuse liability of stimulants in humans correspond to the discriminative stimulus and reinforcing effects of these drugs in laboratory animals. Nevertheless, there are several inconsistencies in the effects of stimulants that suggest that the neuropharmacology underlying subjective and behavioral effects is not the same in laboratory animals and humans. For example, despite the well-documented effects of selective dopamine (DA) antagonists on the discriminative stimulus and reinforcing effects of stimulants in laboratory animals, no studies have shown convincingly that these antagonists alter the subjective effects of stimulants in humans. This suggests that the effects of stimulants on other transmitter systems, such as the serotonin (5-HT) system, may, in part, modulate the subjective effects of stimulants in humans. Indeed, there is preliminary evidence that 5-HT antagonists can attenuate some of the subjective effects of stimulants. The aim of the proposed project is to examine the contribution of the DA and 5-HT systems to the acute subjective effects of methamphetamine, a psychostimulant that is increasingly popular among drug abusers. Like cocaine and d-amphetamine, methamphetamine has effects on both DA and 5-HT systems. As an initial step towards examining the role of 5-HT in the effects of psychostimulants, the proposed studies will compare the acute effects of three antagonists, with a range of relative selectivity for DA and 5-HT receptors, on the subjective effects of methamphetamine in healthy human volunteers. The three antagonists will be haloperidol, risperidone, and mirtazapine. The primary dependent measures will be self-reported ratings of mood and subjective state (e.g. ratings of drug liking and euphoria). Objective measures of drug effects (physiological, motor, and psychomotor) will also be obtained. It is hypothesized that the combined effects of these antagonists on DA and 5-HT systems will result in an attenuation of the subjective effects of methamphetamine.

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