Adaptation to chronic PCP results in hyperfunctional NMDA and hypofunctional GABAA synaptic receptors

B. Yu, C. Wang, J. Liu, K. M. Johnson, J. P. Gallagher

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Schizophrenia is currently thought to be associated with a hypoglutamatergic state that is mimicked by acute phencyclidine (PCP), an antagonist of the N-methyl-D-aspartate (NMDA) receptor subtype. In this study we tested the hypothesis that chronic treatment of rats with this antagonist may be a more appropriate animal model than acute exposure since it could result in adaptive synaptic responses that would model certain aspects of the schizophrenic state in humans. In vitro intracellular electrophysiological recordings employing brain slices from rats treated chronically in vivo with PCP demonstrated that chronic PCP caused a substantial increase in synaptic responses mediated by NMDA receptors without any significant changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-mediated synaptic responses. At the same time, GABAA receptor-mediated inhibitory responses were depressed significantly. Pharmacological and paired-pulse facilitation experiments demonstrated that these adaptive responses following chronic PCP administration were not the result of altered glutamate or GABA release. Immunoblot analyses suggest that the hyperfunctional NMDA response is at least partially mediated by an increased synthesis of NR1 and NR2A subunits as well as a change in the subunit stoichiometry of the NMDA receptor. This change in receptor composition was also supported by pharmacological experiments with a subunit selective NMDA antagonist. Our data support a reconsideration of NMDA and GABAA receptor responsiveness following a chronic, not acute, exposure to PCP and the adaptations that persist after such a regimen.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalNeuroscience
Volume113
Issue number1
DOIs
StatePublished - Aug 2 2002

Keywords

  • Chronic phencyclidine
  • Dorsolateral septal nucleus
  • GABA receptor
  • NMDA receptor
  • Schizophrenia
  • Synaptic transmission

ASJC Scopus subject areas

  • Neuroscience(all)

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