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

S. H. Kim, M. T. Price, J. W. Olney, N. B. Farber

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    70 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
    DOIs
    Publication statusPublished - 1999

    Keywords

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

    ASJC Scopus subject areas

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

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