In order to clarify the possible involvement of N-methyl-D-aspartate (NMDA) receptors in mediating striatal Fos protein induction and behavioral sensitization after methamphetamine administration, we examined the effects of non-competitive NMDA receptor antagonist MK-801 on these phenomena in rats. A single administration of 1.0 and 5.0 mg/kg methamphetamine resulted in a dose-dependent increase in Fos-immunoreactive cells in the medial striatum. Prior exposure to 5.0 mg/kg methamphetamine enhanced ipsilateral rotational behavior in response to subsequent methamphetamine administration in unilateral nigral-lesioned rats (sensitization). Pretreatment with 1.0 mg/kg MK-801 completely prevented both the expression of striatal Fos protein and the development of acute behavioral sensitization following a single injection of 5.0 mg/kg methamphetamine. These results suggest that NMDA receptor-mediated mechanisms contribute to the expression of striatal Fos protein associated with behavioral sensitization that follows exposure to methamphetamine.