CHRONIC PHENCYCLIDINE INDUCES BEHAVIORAL SENSITIZATION AND APOPTOTIC CELL-DEATH IN THE OLFACTORY AND PIRIFORM CORTEX

In this study, we tested the hypothesis that chronic administration of phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) receptor antagoni st, would cause a long-lasting behavioral sensitization associated wit h neuronal toxicity. Female Sprague-Dawley rats were administered PCP (20 mg/kg, i,p,) once a day for 5 days, withdrawn for 72 hr, placed in locomotor activity chambers, and challenged with 3.2 mg/kg PCP, Follo wing assessment of locomotor activity, the rats were killed and their brains processed for analysis of apoptosis by either electron microsco py or terminal dUTP nick-end labeling (TUNEL), In study I, PCP challen ge produced a much more robust and longlasting increase in locomotor a ctivity in rats chronically treated with PCP than in those chronically treated with saline. In study II, clozapine pretreatment blunted the degree of sensitization caused by PCP, In study I, a marked increase i n TUNEL-positive neurons was found in layer II of the olfactory tuberc le and piriform cortex of rats chronically treated with PCP, Many of t hese neurons had crescent-shaped nuclei consistent with apoptotic cond ensation and margination of nuclear chromatin under the nuclear membra ne, Acute PCP had no effect. Electron microscopy revealed that PCP cau sed nuclear condensation and neuronal degeneration consistent with apo ptosis, Cell counts in layer II of the piriform cortex revealed that c hronic PCP treatment resulted in the loss of almost 25% of the cells i n this region. However, an increase in glial fibrillary acidic protein (GFAP)positive cells in the molecular layer suggests that this neurot oxicity also may involve necrosis, In study II, the PCP-induced neuron al degeneration was essentially completely abolished by clozapine pret reatment, This pattern of degeneration was found to coincide with the distribution of the mRNA of the NR1 subunit of the NMDA receptor. The relevance of these data to a PCP model of chronic NMDA receptor hypofu nction is discussed. (C) 1998 Wiley-Liss, Inc.