To assess the possible involvement of NMDA receptors in mediating the expression of striatal c-fos by cocaine injection, we investigated the effects of the noncompetitive NMDA receptor antagonists, ketamine and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), as well as the competitive NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), in the perikarya of cocaine-treated rat brains. As previously shown by our group, administration of 20 mg/kg cocaine (IP) resulted in the immunocytochemical expression of the protooncogene in numerous cells of the caudate putamen (dorsal/sensorimotor striatum). A ketamine mixture anesthetic (2 mg/kg), however, administered 30 min prior to cocaine exposure completely blocked such genomic expression. Pretreatment with MK-801 (1 mg/kg) or CPP (5 mg/kg) also interfered, albeit to a lesser extent, with the expression of c-fos by cocaine in awake animals. These results indicate that cocaine induction of cellular c-fos in the caudate putamen is mediated at least in part by NMDA-sensitive receptors.