The purpose of this study was to evaluate the role of endogenous dopamine in the hypermotility response to MK801. The administration of MK801 (0.1 mg/kg, SC) to rats produced an intense stimulation of coordinated locomotor activity, which was not associated with stereotyped behavior. This stimulatory response was inhibited by pretreatment with either reserpine (5 mg/kg, IP) or alpha-methyl-p-tyrosine (2 doses of 250 mg/kg, IP). Similarly, pretreatment with the D2 antagonist eticlopride (0.03 mg/kg, SC) or the D1 antagonist SCH23390 (0.1 mg/kg, SC) produced a marked inhibition of MK801-stimulated hypermotility, and the combination of eticlopride (0.03 mg/kg, SC) and SCH23390 (0.03 mg/kg, SC) produced a greater inhibition of MK801-stimulated locomotion than either agent alone. The administration of SCH23390 or eticlopride directly into the nucleus accumbens inhibited the locomotor response to MK801, with the combination of both drugs producing a greater inhibition than either agent alone. The intra-accumbens administration of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptor antagonists DNQX or GAMS also inhibited the locomotor response produced by MK801. These data suggest that the activation of D1 and D2 dopaminergic receptors and AMPA/kainate excitatory amino acid receptors in the nucleus accumbens is required for the stimulation of locomotor activity produced by MK801.