Recent experiments have demonstrated that 5-HT 2 A antagonists can modify electrophysiological, neurochemical, and behavioral responses to psychostimulants. These findings led to an interest in using 5-HT 2 A antagonists to block the effects of psychostimulants on brain reward mechanisms. The present experiments assessed the ability of mixed D 2 /5-HT 2 A antagonists to reverse amphetamine-induced facilitation of self-stimulation. The D 2 /5-HT 2 A antagonists MDL 28,133A and risperidone attenuated the effects of cocaine and amphetamine, but only at antagonist doses that elevated baseline self-stimulation thresholds. A comparison of the effects of the mixed antagonists to those of haloperidol and eticlopride revealed that all four antagonists produced similar anti-stimulant effects when the influence of the drugs on baseline responding was considered. The D 2 activity of the antagonists appears to account for their ability to reduce the effects of psychostimulants on self-stimulation. 5-HT 2 A antagonism makes a negligible contribution to the anti-amphetamine effects.