Excessive cerebrocortical release of acetylcholine induced by NMDA antagonists is reduced by GABAergic and α2-adrenergic agonists

Seung Hyun Kim, M. T. Price, J. W. Olney, N. B. Farber

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

N-methyl-D-aspartate (NMDA) glutamate (Glu) receptor antagonists (eg MK-801, ketamine, phencyclidine [PCP]) injure cerebrocortical neurons in the posterior cingulate and retrosplenial cortex (PC/RSC). We have proposed that the neurotoxic action of these agents is mediated in part by a complex polysynaptic mechanism involving an interference in GABAergic inhibition resulting in excessive release of acetylcholine (ACh). Previously we have found that the systemic injection of GABAergic agents and α2-adrenergic agonists can block this neurotoxicity. In the present study we tested the hypothesis that NMDA antagonists trigger release of ACh in PC/RSC and that this action of NMDA antagonists is suppressed by GABAergic agents or α2-adrenergic agonists. The effect of MK-801 and ketamine on PC/RSC ACh output (and the ability of pentobarbital, diazepam and clonidine to modify MK-801-induced ACh release) was studied in adult female rats using in vivo microdialysis. Both MK-801 and ketamine caused a significant rise in PC/RSC ACh output compared to basal levels. Pentobarbital, diazepam and clonidine suppressed MK-801's effect on ACh release. Exploratory studies indicated that the site of action of these agents was outside of the PC/RSC. The microdialysis results are consistent with several aspects of the circuitry proposed to mediate the neurotoxic action of NMDA antagonists.

Original languageEnglish
Pages (from-to)344-352
Number of pages9
JournalMolecular Psychiatry
Volume4
Issue number4
Publication statusPublished - 1999 Sep 29

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Keywords

  • Alzheimer's disease
  • Ketamine
  • Microdialysis
  • MK-801
  • Neurotoxicity
  • NMDA antagonists
  • Posterior cingulate
  • Retrosplenial cortex
  • Schizophrenia

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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