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Research ArticleNEUROPHARMACOLOGY

Mechanisms ofN-Methyl-d-aspartate-Induced Apoptosis in Phencyclidine-Treated Cultured Forebrain Neurons

Cheng Wang, Joel A. Kaufmann, Monica G. Sanchez-Ross and Kenneth M. Johnson
Journal of Pharmacology and Experimental Therapeutics July 2000, 294 (1) 287-295;
Cheng Wang
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Joel A. Kaufmann
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Monica G. Sanchez-Ross
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Kenneth M. Johnson
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Abstract

Chronic administration of phencyclidine (PCP) to rats has been demonstrated to produce a sensitized locomotor response to PCP challenge that is associated with apoptotic cell death and an up-regulation of the N-methyl-d-aspartate (NMDA) receptor. To determine the underlying mechanisms, dissociated forebrain cultures were treated for 2 days with 3 μM PCP. After washout of PCP, NMDA was added (in the presence of Mg2+) for 20 h. The uptake of a vital dye and the release of lactate dehydrogenase measured cell viability. Apoptosis was assessed by an enzyme-linked immunosorbent assay that was specific for fragmented (histone-associated) DNA and an in situ assay for nicked DNA, terminal dUTP nick-end labeling. These assays showed that the effect of a nontoxic concentration of NMDA (30 μM) became lethal to approximately one-third of the neurons after chronic (48-h) PCP treatment. This treatment also resulted in a 47% increase in NR1 subunit mRNA, suggesting that NMDA-induced neuronal cell death after chronic PCP is due to NMDA receptor up-regulation. Furthermore, exposure of PCP-treated cultures to NMDA led to increased expression of Bax and decreased expression of Bcl-XL. The Bcl-XL/Bax ratio was markedly decreased by 30 μM NMDA in the PCP-treated, but not control, cultures. Addition of superoxide dismutase and catalase prevented the decrease in Bcl-XL/Bax. This study suggests that NMDA-induced changes in Bax and/or Bcl-XL involve the formation of reactive oxygen species. By extrapolation, these data suggest that PCP-induced apoptosis in vivo may involve similar mechanisms and that cultured neurons may be a suitable model for the mechanistic study PCP toxicity in vivo.

Footnotes

  • Send reprint requests to: Kenneth M. Johnson, Ph.D., Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555-1031. E-mail:kmjohnso{at}utmb.edu

  • ↵1 This study was supported by National Institutes of Health Grant DA 02073 and the John Sealy Memorial Endowment Fund for Biomedical Research.

  • ↵2 Current address: Neuroscience Graduate Program, University of Texas Medical Branch, Galveston, TX 77555-1031.

  • Abbreviations:
    PCP
    phencyclidine
    NMDA
    N-methyl-d-aspartate
    DMEM
    Dulbecco's modified Eagle's medium
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    LDH
    lactate dehydrogenase
    ELISA
    enzyme-linked immunosorbent assay
    TUNEL
    terminal dUTP nick-end labeling
    PSA-NCAM
    polysialic acid-neuronal cell adhesion molecule
    ROS
    reactive oxygen species
    SOD
    superoxide dismutase
    NF-κB
    nuclear factor-κB
    • Received November 16, 1999.
    • Accepted March 15, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 1
1 Jul 2000
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Research ArticleNEUROPHARMACOLOGY

Mechanisms ofN-Methyl-d-aspartate-Induced Apoptosis in Phencyclidine-Treated Cultured Forebrain Neurons

Cheng Wang, Joel A. Kaufmann, Monica G. Sanchez-Ross and Kenneth M. Johnson
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 287-295;

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Research ArticleNEUROPHARMACOLOGY

Mechanisms ofN-Methyl-d-aspartate-Induced Apoptosis in Phencyclidine-Treated Cultured Forebrain Neurons

Cheng Wang, Joel A. Kaufmann, Monica G. Sanchez-Ross and Kenneth M. Johnson
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 287-295;
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