The Neurotoxicity Induced by Ethanol Withdrawal in Mature Organotypic Hippocampal Slices Might Involve Cross-Talk between Metabotropic Glutamate Type 5 Receptors and N-Methyl-D-Aspartate Receptors

Barton R. Harris, D. Alex Gibson, Mark A. Prendergast, John A. Blanchard, Robert C. Holley, Stewart R. Hart, Rebecca L. Scotland, Thomas C. Foster, Norman W. Pedigo, John M. Littleton

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

Abstract

Background: We recently reported that the sodium salt of acamprosate (Na-acamprosate) demonstrates the characteristics of an antagonist at metabotropic glutamate type 5 receptors (mGluR5s) rather than at N-methyl-D-aspartate receptors (NMDARs). Because mGluR5s are able to enhance the function of NMDARs, this interplay may be involved in the dysregulation of glutamatergic transmission during ethanol withdrawal. The following studies use organotypic hippocampal slice cultures at a mature age to investigate the potential for this interplay in the neurotoxicity associated with withdrawal from long-term ethanol exposure. Methods: At 25 days in vitro, organotypic hippocampal slice cultures prepared from male and female 8-day-old rats were exposed to an initial concentration of 100 mM ethanol for 10 days before undergoing a 24-hr period of withdrawal. The effects of Na-acamprosate; 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893), a noncompetitive antagonist at mGluR5s; 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester, a noncompetitive antagonist at mGluR1s; dizocilpine (MK-801), a noncompetitive NMDAR antagonist; and staurosporine on the neurotoxicity induced by ethanol withdrawal were assessed by determining differences in propidium iodide uptake. Polypeptide levels of mGluR5s and the NR1 and NR2B subunits of NMDARs were also determined via Western blot analyses after 10 days of ethanol exposure. Results: Significant neurotoxicity was always evident in the CA1 hippocampal region after a 24-hr withdrawal period. This spontaneous neurotoxicity resulted from intrinsic changes induced by the long-term presence of ethanol. Na-acamprosate (200-1000 μM), SIB-1893 (200-500 μM), MK-801 (20 μM), and staurosporine (200 nM) were all neuroprotective. The polypeptide levels of mGluR5s and NR1 and NR2B subunits of NMDARs were all increased after ethanol exposure; however, the increase in mGluR5s did not achieve statistical significance. Conclusions: From this model of long-term ethanol exposure and withdrawal, the functional interplay between mGluR5s and NMDARs might represent a novel target for the prevention of neurotoxicity associated with ethanol withdrawal.

Original languageEnglish
Pages (from-to)1724-1735
Number of pages12
JournalAlcoholism: Clinical and Experimental Research
Volume27
Issue number11
DOIs
StatePublished - Nov 2003

Funding

FundersFunder number
National Institute on Alcohol Abuse and AlcoholismF31AA013365

    Keywords

    • Acamprosate
    • Ethanol Withdrawal
    • Hippocampus
    • NMDAR
    • mGluR5

    ASJC Scopus subject areas

    • Medicine (miscellaneous)
    • Toxicology
    • Psychiatry and Mental health

    Fingerprint

    Dive into the research topics of 'The Neurotoxicity Induced by Ethanol Withdrawal in Mature Organotypic Hippocampal Slices Might Involve Cross-Talk between Metabotropic Glutamate Type 5 Receptors and N-Methyl-D-Aspartate Receptors'. Together they form a unique fingerprint.

    Cite this