EFFECTS OF PHENCYCLIDINE ON IMMEDIATE-EARLY GENE-EXPRESSION IN THE BRAIN

The N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) is a psychotomimetic drug which produces schizophrenia-like psychosis. In a nimal studies it is toxic to neurons in the posterior cingulate and re trosplenial cortex and to cerebellar Purkinje cells. To find clues abo ut 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 histo chemistry. 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 I EGs was observed 30 min after drug treatment in the cerebral cortex an d in the hippocampus. c-fos, NGFI-A, and NGFI-B were also induced in t halamic nuclei, and c-fos was also induced in the cerebellar granule c ell layer. In contrast, a delayed induction of c-fos, c-jun, NGFI-A, N GFI-B, NGFI-C, and Nurr1 in the posterior cingulate cortex was observe d 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 olivar y nucleus. PCP-induced IEG expression returned to baseline by 24 hr. A lower PCP dose, 10 mg/kg, induced lower levels of LEG expression, wit h similar anatomical and biphasic temporal pattern as with the higher PCP dose of 50 mg/kg. However, no IEG induction was observed in the hi ppocampus following 10 mg/kg PCP. These results demonstrate that PCP p roduces neural activation not only in the cingulate and retrosplenial cortex, but also in many other regions of forebrain and cerebellum. Mo reover, prolonged IEG expression in the posterior cingulate cortex and cerebellar Purkinje cells, the sites of PCP toxicity, suggests that I EGs could mediate neurotoxic/neuroprotective effects in these brain re gions. (C) 1996 Wiley-Liss, Inc.