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Research ArticleArticle

Evidence for a Causative Role of N-Methyl-d-aspartate Receptors in an In Vitro Model of Alcohol Withdrawal Hyperexcitability

Mark P. Thomas, Daniel T. Monaghan and Richard A. Morrisett
Journal of Pharmacology and Experimental Therapeutics October 1998, 287 (1) 87-97;
Mark P. Thomas
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Daniel T. Monaghan
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Richard A. Morrisett
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Abstract

Synaptic mechanisms underlying hyperexcitability due to withdrawal from chronic ethanol exposure were investigated in a hippocampal explant model system using electrophysiological techniques. Whole-cell voltage clamp recordings from CA1 pyramidal cells demonstrated that acute ethanol exposure inhibited N-methyl-d-aspartate receptor (NMDAR)-mediated excitatory postsynaptic currents by over 40%. Chronic ethanol exposure for 6 to 11 days at 35 or 75 mM induced no differences from control explants in the fast component of the population synaptic response (non-NMDAR-mediated). Prolonged field potential recordings (to 10 hr) were used to monitor the withdrawal process in vitro. Ethanol-exposed explants from both 35 and 75 mM groups displayed an increase (60% and 89%, respectively) in the NMDAR-mediated component of synaptic transmission on withdrawal from chronic exposure. Prolonged tonic-clonic electrographic seizure activity was consistently observed after ethanol withdrawal only after the increase in NMDAR function. This hyperexcitability was inhibited by the NMDAR antagonist d-2-amino-5-phosphonovaleric acid and returned once the NMDAR component was reestablished after antagonist washout. In situ hybridization studies suggest that expression of NR2B subunit mRNA may be enhanced in explants after chronic ethanol exposure. No lasting differences were observed in the NMDAR component after acute in vitro ethanol exposure and withdrawal. These data suggest that the occurance of ethanol withdrawal hyperexcitability in this system may be directly dependent on alterations in NMDAR function after chronic exposure. Since this region and others that contain ethanol sensitive NMDARs may serve as epileptic foci, long term alterations in NMDAR function may be expected to generate paroxysmal depolarizing shifts underlying ictal events after withdrawal from ethanol exposure.

Footnotes

  • Send reprint requests to: Richard Morrisett, Ph.D., Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, TX 78712-1074. E-mail:ramorris{at}mail.utexas.edu

  • ↵1 This work was supported by Grant R299230 from the National Institute of Alcohol Abuse and Alcoholism to R.A.M.

  • ↵2 Present address: The Department of Pharmacology, University of Nebraska Medical Center, Omaha, NE 68 198-6260.

  • ↵3 Present address: The Institute for Neuroscience, and the Division of Pharmacology, and Toxicology, College of Pharmacy, University of Texas, Austin, TX 78712-1074.

  • Abbreviations:
    ACSF
    artificial cerebrospinal fluid
    CE
    chronic ethanol-treated
    D-APV
    d-2-amino-5-phosphonovaleric acid
    DNQX
    6,7-dinitroquinoxaline-2,3(1H,4H)-dione
    EGS
    electrographic seizure
    EPSC
    excitatory postsynaptic current
    GABA
    gamma-aminobutyric acid
    NMDAR
    N-methyl-d-aspartate receptor
    PBS
    phosphate-buffered saline
    PS
    population spike
    PSP
    postsynaptic potential
    SSC
    saline-sodium citrate
    • Received February 12, 1998.
    • Accepted May 22, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 1
1 Oct 1998
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Research ArticleArticle

Evidence for a Causative Role of N-Methyl-d-aspartate Receptors in an In Vitro Model of Alcohol Withdrawal Hyperexcitability

Mark P. Thomas, Daniel T. Monaghan and Richard A. Morrisett
Journal of Pharmacology and Experimental Therapeutics October 1, 1998, 287 (1) 87-97;

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Research ArticleArticle

Evidence for a Causative Role of N-Methyl-d-aspartate Receptors in an In Vitro Model of Alcohol Withdrawal Hyperexcitability

Mark P. Thomas, Daniel T. Monaghan and Richard A. Morrisett
Journal of Pharmacology and Experimental Therapeutics October 1, 1998, 287 (1) 87-97;
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