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

Chronic administration of the NMDA receptor antagonist phencyclidine (PCP) in rats activates the ERK signaling pathway specifically in the cerebellum, but not in other brain regions. Using osmotic pumps to deliver PCP continuously for 10 or 20 days at 18 mg/kg/day, phosphorylation of ERK1, ERK2, and MEK increased significantly in the cerebellum, with no change at 3 days. Dose-dependent elevation of ERK1 and ERK2 phosphorylation occurred in the cerebellum at 2.5, 10, 18, or 25 mg/kg/day over 10 days, while JNK and p38 activities remained unchanged across all brain regions examined. These findings suggest a role for ERK signaling in PCP's effects and possibly in schizophrenia.

Study at a glance

Abstract

We have previously demonstrated elevation of the extracellular signal-regulated kinase (ERK) pathway in the cerebellum from patients with schizophrenia, an illness that may involve dysfunction of the N-methyl-D-aspartate (NMDA) receptor. Since the NMDA antagonist, phencyclidine (PCP), produces schizophrenic-like symptoms in humans, and abnormal behavior in animals, we examined the effects of chronic PCP administration in time- and dose-dependent manner on ERK and two other members of mitogen-activated protein kinase family, c-Jun N-terminal protein kinase (JNK) and p38, in rat brain. Osmotic pumps for PCP (18 mg/kg/day) and saline (controls) were implanted subcutaneously in rats for three, 10, and 20 days. Using Western blot analysis, we found no change at three days, but a significant increase in the phosphorylation of ERK1, ERK2 and MEK in the cerebellum at 10- and 20-days of continuous PCP infusion. For the experiments involving various doses of PCP, rats were infused with PCP at concentrations of 2.5, 10, 18, or 25 mg/kg/day, or saline for 10 days. We observed a dose-dependent elevation in the phosphorylation 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 region-specific activation of MAP kinases, suggesting a role for the ERK signaling pathway in PCP abuse and perhaps in schizophrenia.