Chronic phencyclidine increases NMDA receptor NR1 subunit mRNA in rat forebrain

The present study was designed to determine whether the sensitization of locomotor activity that results from chronic phencyclidine (PCP) administration is associated with altered NMDA receptor function or mRNA in rat brain. Female Sprague-Dawley rats were administered PCP (20 mg/kg, i.p.) once daily for 5 days. After withdrawal for 72 hr, challenge with 3.2 mg/kg PCP (i.p.) revealed a significant sensitization to the locomotor activating effect of PCP. In situ hybridization analysis with an oligonucleotide probe complementary to the mRNA encoding the NR1 subunit of the NMDA receptor demonstrated that chronic PCP treatment resulted in a marked increase in NR1 subunit mRNA in the forebrain. Quantitative image analysis revealed a significant increase in the labeling of NR1 mRNA in the olfactory tubercle, piriform cortex, frontal cortex, and anterior striatum. However, no significant difference between PCP and saline-treated rats was found in the hippocampus or cerebellum. In a parallel study, possible functional alterations in the NMDA receptor were assessed by measuring NMDA-stimulated release of [³H]DA from slices of the olfactory tubercle and piriform cortex. NMDA-stimulated release was not affected by chronic PCP treatment, but the inhibition of this release by PCP, 7-chlorokynurenic acid (7-CK), and DL-2- amino-5-phosphovaleric acid (AP-5) was significantly diminished by chronic PCP. This suggests that the behavioral plasticity associated with chronic PCP may be related to an altered subunit stoichiometry of NMDA receptors in selective forebrain regions.