PMID- 9669320 OWN - NLM STAT- MEDLINE DCOM- 19980925 LR - 20131121 IS - 0360-4012 (Print) IS - 0360-4012 (Linking) VI - 52 IP - 6 DP - 1998 Jun 15 TI - Chronic phencyclidine induces behavioral sensitization and apoptotic cell death in the olfactory and piriform cortex. PG - 709-22 AB - In this study, we tested the hypothesis that chronic administration of phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) receptor antagonist, would cause a long-lasting behavioral sensitization associated with 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 Female Sprague-Dawley rats were administered PCP (20 mg/kg, i.p.) once a day for 5 days, withdrawn for 72 hr, placed in locomotor activity chambers, and challenged with 3.2 mg/kg PCP. Following assessment of locomotor activity, the rats were killed and their brains processed for analysis of apoptosis by either electron microscopy or terminal dUTP nick-end labeling (TUNEL). In study I, PCP challenge produced a much more robust and long-lasting increase in locomotor activity 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 in TUNEL-positive neurons was found in layer II of the olfactory tubercle and piriform cortex of rats chronically treated with PCP. Many of these neurons had crescent-shaped nuclei consistent with apoptotic condensation and margination of nuclear chromatin under the nuclear membrane. Acute PCP had no effect. Electron microscopy revealed that PCP caused nuclear condensation and neuronal degeneration consistent with apoptosis. Cell counts in layer II of the piriform cortex revealed that chronic PCP treatment resulted in the loss of almost 25% of the cells in this region. However, an increase in glial fibrillary acidic protein (GFAP)-positive cells in the molecular layer suggests that this neurotoxicity also may involve necrosis. In study II, the PCP-induced neuronal degeneration was essentially completely abolished by clozapine pretreatment. 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 hypofunction is discussed. FAU - Johnson, K M AU - Johnson KM AD - Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston 77555-1031, USA. FAU - Phillips, M AU - Phillips M FAU - Wang, C AU - Wang C FAU - Kevetter, G A AU - Kevetter GA LA - eng GR - R01 DA 02073/DA/NIDA NIH HHS/United States GR - T32 DA 07287/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - J Neurosci Res JT - Journal of neuroscience research JID - 7600111 RN - 0 (Antipsychotic Agents) RN - 0 (Excitatory Amino Acid Antagonists) RN - J1DOI7UV76 (Phencyclidine) RN - J60AR2IKIC (Clozapine) SB - IM MH - Animals MH - Antipsychotic Agents/pharmacology MH - *Apoptosis/*physiology MH - Behavior, Animal/*drug effects MH - Clozapine/pharmacology MH - Drug Resistance/physiology MH - Excitatory Amino Acid Antagonists/*pharmacology MH - Female MH - Genetic Techniques MH - Limbic System/*drug effects/pathology MH - Microscopy, Electron MH - Motor Activity/drug effects MH - Nerve Degeneration/prevention & control MH - Olfactory Pathways/*drug effects/pathology MH - Phencyclidine/*pharmacology MH - Rats MH - Rats, Sprague-Dawley MH - Time Factors EDAT- 1998/07/21 02:16 MHDA- 2000/06/20 09:00 CRDT- 1998/07/21 02:16 PHST- 1998/07/21 02:16 [pubmed] PHST- 2000/06/20 09:00 [medline] PHST- 1998/07/21 02:16 [entrez] AID - 10.1002/(SICI)1097-4547(19980615)52:6<709::AID-JNR10>3.0.CO;2-U [pii] AID - 10.1002/(SICI)1097-4547(19980615)52:6<709::AID-JNR10>3.0.CO;2-U [doi] PST - ppublish SO - J Neurosci Res. 1998 Jun 15;52(6):709-22. doi: 10.1002/(SICI)1097-4547(19980615)52:6<709::AID-JNR10>3.0.CO;2-U.