The N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) is a psychotomimetic drug which produces schizophrenia-like psychosis. In animal studies it is toxic to neurons in the posterior cingulate and retrosplenial cortex and to cerebellar Purkinje cells. To find clues about the mechanism and pathways of PCP action, we studied the effect of systemic PCP administration (10 and 50 mg/kg, intraperitoneal) on the expression of immediate-early genes (IEGs) (c-fos, c-jun, egr-2, egr-3, NGFI-A, NGFI-B, NGFI-C, and Nurr1) using in situ hybridization histochemistry. PCP, 50 mg/kg, produced a biphasic IEG induction: an early induction in the hippocampus, cerebral cortex, and cerebellar granule cell layer, and a delayed induction in the posterior cingulate cortex and cerebellar Purkinje cell layer. The early induction of all eight IEGs was observed 30 min after drug treatment in the cerebral cortex and in the hippocampus. c-fos, NGFI-A, and NGFI-B were also induced in thalamic nuclei, and c-fos was also induced in the cerebellar granule cell layer. In contrast, a delayed induction of c-fos, c-jun, NGFI-A, NGFI-B, NGFI-C, and Nurr1 in the posterior cingulate cortex was observed 2-6 hr after PCP, 50 mg/kg. egr-2 and egr-3 were not induced in the posterior cingulate cortex. c-fos induction in the cerebellar Purkinje cell layer peaked 2 hr after PCP, 50 mg/kg. In addition, PCP induced c-fos, egr-3, NGFI-A, NGFI-B, NGFI-C, and Nurr1 in the inferior olivary nucleus. PCP-induced IEG expression returned to baseline by 24 hr. A lower PCP dose, 10 mg/kg, induced lower levels of IEG expression, with similar anatomical and biphasic temporal pattern as with the higher PCP dose of 50 mg/kg. However, no IEG induction was observed in the hippocampus following 10 mg/kg PCP. These results demonstrate that PCP produces neural activation not only in the cingulate and retrosplenial cortex, but also in many other regions of forebrain and cerebellum. Moreover, prolonged IEG expression in the posterior cingulate cortex and cerebellar Purkinje cells, the sites of PCP toxicity, suggests that IEGs could mediate neurotoxic/neuroprotective effects in these brain regions.