Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists, like phencyclidine (PCP), elicit schizophrenia-like symptoms in humans and behavioral abnormalities in animals, such as hyperactivity. We investigated the effect of the atypical antipsychotic risperidone on hyperlocomotion produced in mice by 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801), an NMDA receptor antagonist. MK-801 (0.125, 0.25, 0.50 mg/kg) dose-dependently increased the total distance traveled in an open field during a 90 min period in mice. The increase in MK-801 (0.25 mg/kg)-induced total distance traveled was attenuated by pretreatment with risperidone at doses that alone had no effect on spontaneous locomotor activity. Furthermore, (+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), a serotonin 5-HT(2A/2C) receptor agonist, at the doses that failed to change spontaneous locomotor activity or hyperlocomotion induced by MK-801, reversed the attenuation by risperidone. The serotonin 5-HT(2A/2C) receptor antagonist, ritanserin, enhanced the inhibitory effect of risperidone. These findings indicate that risperidone attenuates MK-801-induced hyperlocomotion in mice by blocking serotonin 5-HT(2A/2C) receptors.