Risperidone attenuates the discriminative-stimulus effects of d-amphetamine in humans

Studies conducted with nonhuman laboratory animals have consistently shown that atypical antipsychotics that are mixed dopamine and serotonin antagonists attenuate the discriminative-stimulus effects of amphetamine. In the present experiment, eight healthy humans learned to discriminate 15 mg of oral d-amphetamine. After acquiring the discrimination (i.e., ≥80% correct responding on four consecutive days), the effects of a range of doses of d-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and after pretreatment with risperidone (0 and 1 mg), a D₂ dopamine and 5-hydroxytryptamine (5-HT)₂ serotonin antagonist, were assessed. d-Amphetamine alone functioned as a discriminative stimulus and produced stimulant-like self-reported drug effects (e.g., increased ratings of "like drug"). These effects were generally a function of dose. Risperidone alone did not occasion d-amphetamine-appropriate responding, but impaired performance. Risperidone pretreatment significantly attenuated the discriminative-stimulus effects of d-amphetamine, and some of the self-reported drug effects. The results of the present experiment suggest that combining drug-discrimination and self-reported drug-effect questionnaires may be an effective strategy for assessing the behavioral effects of agonist-antagonist interactions. Future studies should compare the behavioral effects of d-amphetamine after pretreatment with a selective D₂ dopamine (e.g., haloperidol) or 5-HT₂ serotonin (e.g., ritanserin) antagonist to determine the relative contribution of dopamine and serotonin systems in mediating the behavioral effects of stimulants in humans. The results of these studies might guide the development of a pharmacotherapy for the treatment of amphetamine abuse/dependence.