Differential and region-specific activation of mitogen-activated protein kinases following chronic administration of phencyclidine in rat brain

We have previously demonstrated elevation of the extracellular signal-regul ated kinase (ERK) pathway in the cerebellum from patients with schizophreni a, an illness that may involve dysfunction of the N-methyl-D-aspartate (NMD A) receptor. Since the NMDA antagonist, phencyclidine (PCP), produces schiz ophrenic-like symptoms in humans, and abnormal behavior in animals, we exam ined the effects of chronic PCP administration in time- and dose-dependent manner on ERK and two other members of mitogen-activated protein kinase fam ily, c-Jun N-terminal protein kinase (JNK) and p38, in rat brain. Osmotic p umps for PCP (18 mg/kg/day) and saline (controls) were implanted subcutaneo usly in rats for three, 10, and 20 days. Using Western blot analysis, we fo und no change at three days, but a significant increase in the phosphorylat ion of ERK1, ERK2 and MEK in the cerebellum at 10- and 20-days of continuou s PCP infusion. For the experiments involving various doses of PCP; rats we re infused with PCP at concentrations of 2.5, 10, 18, or 25 mg/kg/day, or s aline for 10 days. We observed a dose dependent elevation in the phosphoryl ation of ERK1 and ERK2 only in the cerebellum but not in brainstem, frontal cortex or hippocampus. The activities of JNK and p38 were unchanged in all investigated brain regions including cerebellum. These results demonstrate that chronic infusion of PCP in rats produces a differential and brain reg ion-specific activation of MAP kinases, suggesting a role for the ERK signa ling pathway in PCP abuse and perhaps in schizophrenia. (C) 2001 American C ollege of Neuropsychopharmacology. Published by Elsevier Science Inc.