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Research ArticleNEUROPHARMACOLOGY

Ifenprodil and Ethanol Enhance NMDA Receptor-Dependent Long-Term Depression

Adam W. Hendricson, C. L. Alek Miao, Melanie J. Lippmann and Richard A. Morrisett
Journal of Pharmacology and Experimental Therapeutics June 2002, 301 (3) 938-944; DOI: https://doi.org/10.1124/jpet.301.3.938
Adam W. Hendricson
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C. L. Alek Miao
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Melanie J. Lippmann
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Richard A. Morrisett
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Abstract

Long-term alterations in synaptic transmission are thought to underlie various types of alcohol-related brain disorders. While ethanol effects on synaptic potentiation are well documented, ethanol effects on synaptic depression have not been addressed. Herein, we performed experiments to assess the role of ethanol on long-term depression (LTD) formation. In rat hippocampal slices, prolonged low-frequency stimulation (LFS) of CA1 Schaffer collaterals (1 Hz for 7 min) induced saturable, long-lasting, reversibleN-methyl-d-aspartate (NMDA) receptor-dependent LTD of stimulus-evoked dendritic population excitatory postsynaptic potentials. This depression (−26% LTD amplitude) was observed in young rats (12–20 days old), but not adult rats (28–35 days old). Induction of LTD was blocked (−3% LTD amplitude) when the LFS was delivered in the presence of the NMDA receptor antagonist d-2-amino-5-phosphonovaleric acid. When the conditioning LFS was delivered in the presence of ethanol, there was a significant enhancement in the induction of NMDA receptor-dependent LTD versus control LTD (−36% LTD amplitude). Ifenprodil, an N-methyl-d-aspartate receptor subunit 2B (NR2B)-selective antagonist, also significantly facilitated the induction of LTD (−40% LTD amplitude). Consistent with this result, ifenprodil did not affect the NMDA receptor-dependent component of the baseline synaptic response, whereasd-2-amino-5-phosphonovaleric acid caused significant depression of the NMDA component. These data indicate that whereas ethanol is known to inhibit NMDA receptor function in a variety of systems, it significantly enhances the induction of NMDA receptor-dependent LTD. Furthermore, since ifenprodil is known to select for ethanol-sensitive subtypes of NR2B-NMDA receptors, these data also suggest that NR2B-containing NMDA receptor subpopulations do not contribute to LTD, but instead may actually play inhibitory roles in LTD induction.

Footnotes

  • This work was supported by Grants R01AA11845 and R01AA09230 from the National Institute of Alcohol Abuse and Alcoholism (to R.A.M.).

  • Abbreviations:
    LTD
    long-term depression
    ACSF
    artificial cerebrospinal fluid
    AMPA
    α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
    d-APV
    d-2-amino-5-phosphonovaleric acid
    pEPSP
    population excitatory postsynaptic potential
    LFS
    low-frequency stimulation
    mGlu
    metabotropic glutamate
    NMDA
    N-methyl-d-aspartate
    LTP
    long-term potentiation
    NR2B and NR2C/D
    N-methyl-d-aspartate receptor subunits 2B and C/D
    • Received November 8, 2001.
    • Accepted February 14, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 3
1 Jun 2002
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Research ArticleNEUROPHARMACOLOGY

Ifenprodil and Ethanol Enhance NMDA Receptor-Dependent Long-Term Depression

Adam W. Hendricson, C. L. Alek Miao, Melanie J. Lippmann and Richard A. Morrisett
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 938-944; DOI: https://doi.org/10.1124/jpet.301.3.938

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Research ArticleNEUROPHARMACOLOGY

Ifenprodil and Ethanol Enhance NMDA Receptor-Dependent Long-Term Depression

Adam W. Hendricson, C. L. Alek Miao, Melanie J. Lippmann and Richard A. Morrisett
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 938-944; DOI: https://doi.org/10.1124/jpet.301.3.938
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