Chronic phencyclidine induces behavioral sensitization and apoptotic cell death in the olfactory and piriform cortex

Kenneth M. Johnson, Melissa Phillips, Cheng Wang, Golda A. Kevetter

Research output: Contribution to journalArticle

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Abstract

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 Female Sprague-Dawley rats were administered PCP (20 mg/kg, i.p.) once a day for 5 days, withdrawn for 72 hr, placed in locomotor activity chambers, and challenged with 3.2 mg/kg PCP.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.

Original languageEnglish (US)
Pages (from-to)709-722
Number of pages14
JournalJournal of Neuroscience Research
Volume52
Issue number6
DOIs
StatePublished - Jun 15 1998

Fingerprint

Phencyclidine
Locomotion
N-Methyl-D-Aspartate Receptors
Cell Death
Clozapine
Electron Microscopy
Apoptosis
Neurons
Glial Fibrillary Acidic Protein
Nuclear Envelope
Chromatin
Sprague Dawley Rats
Necrosis
Cell Count
Messenger RNA
Brain
Piriform Cortex
Olfactory Cortex

Keywords

  • Apoptosis
  • Dopamine
  • Neurotoxicity
  • NMDA receptors
  • Olfactory tubercle
  • Phencyclidine
  • Piriform cortex
  • Programmed cell death
  • Sensitization

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Chronic phencyclidine induces behavioral sensitization and apoptotic cell death in the olfactory and piriform cortex. / Johnson, Kenneth M.; Phillips, Melissa; Wang, Cheng; Kevetter, Golda A.

In: Journal of Neuroscience Research, Vol. 52, No. 6, 15.06.1998, p. 709-722.

Research output: Contribution to journalArticle

Johnson, Kenneth M. ; Phillips, Melissa ; Wang, Cheng ; Kevetter, Golda A. / Chronic phencyclidine induces behavioral sensitization and apoptotic cell death in the olfactory and piriform cortex. In: Journal of Neuroscience Research. 1998 ; Vol. 52, No. 6. pp. 709-722.
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