Glutamate receptor subunits are altered in forebrain and cerebellum in rats chronically exposed to the NMDA receptor antagonist phencyclidine.

Abstract

Phencyclidine (PCP) is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype. It produces transient psychoses in normal individuals and exacerbates psychoses in schizophrenics. When administered to rodents, PCP elicits stereotypic behaviors including unrelenting head swaying, hyperlocomotion, and social withdrawal. In this study, we examined the relative distribution of the NMDA receptor subunits, as well as the subunits of its modulating receptor, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) in the forebrain, hippocampus, and cerebellum of rats chronically exposed to PCP. Rats were injected for 30 days with PCP (10 mg/kg) and age/sex-matched controls were injected for 30 days with saline vehicle. Brain NMDA and AMPA receptor subunit distribution patterns and protein levels were then analyzed by immunocytochemistry and Western blot analysis. Chronic PCP-treated animals showed significant alterations in glutamate receptor subunits, particularly for the NR1, NR2B, NR2C, and NR2D components of the NMDA receptor. AMPA receptor subunits demonstrated few significant changes in subunit availabilities. Western blot analysis largely confirmed the immunocytochemical findings. These results support the conclusion that subunits of the NMDA receptor are selectively altered by chronic PCP antagonism, with minimal to no changes observed in AMPA receptor subunits. Our findings are consistent with the interpretation that a dysfunctional NMDA receptor complex may mediate abnormal glutamatergic neurotransmission and potentially contribute to the complex etiology of cognitive disorders.