Neuroleptic blockade of dopamine receptors is known to produce an increase in the expression of Fos. This increase may be related to elevations in glutamate transmission which in turn activates N-methyl-D-aspartate (NMDA) receptors. In the present study, we examine the role of these receptors in the haloperidol-induced augmentation of Fos in the caudate-putamen and nucleus accumbens of Wistar rats. Animals were divided into four groups for each experiment and each was injected either with saline; a noncompetitive NMDA antagonist, dizocilpine maleate (MK801, 5 mg/kg); haloperidol (0.5 mg/kg); or MK801 followed by an injection of haloperidol. Fos-immunoreactive cells appear in large numbers in all parts of the striatum 3 h after the administration of haloperidol. Pretreatment with MK801 attenuates the haloperidol-induced increase in Fos in the caudate-putamen. However, antagonism of the NMDA receptor does not significantly reduce the density of Fos-immunoreactive cells in any territory of nucleus accumbens, i.e., shell, core, or rostral pole. These data suggest that haloperidol acts in an NMDA-dependent manner in the caudate-putamen, but independently in parts of nucleus accumbens traditionally considered to be targets of antipsychotic drugs.