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Research ArticleNEUROPHARMACOLOGY

Group II Metabotropic Glutamate Receptors Modulate Extracellular Glutamate in the Nucleus Accumbens

Zheng-Xiong Xi, David A. Baker, Hui Shen, Daniel S. Carson and Peter W. Kalivas
Journal of Pharmacology and Experimental Therapeutics January 2002, 300 (1) 162-171; DOI: https://doi.org/10.1124/jpet.300.1.162
Zheng-Xiong Xi
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David A. Baker
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Hui Shen
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Daniel S. Carson
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Peter W. Kalivas
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Abstract

The regulation of extracellular glutamate in the nucleus accumbens by group II metabotropic glutamate receptors (mGluR2/3) was examined in vivo. Stimulation of mGluR2/3 with 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) or N-acetylaspartylglutamate reduced extracellular glutamate levels. Conversely, blockade of mGluR2/3 by LY143495 or (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA) increased extracellular glutamate, an effect antagonized by the coadministration of APDC. These effects likely involve both vesicular and nonvesicular glutamate, because the increase in glutamate by APICA or the decrease by APDC was prevented by blocking N-type calcium channels and the release of glutamate after potassium-induced membrane depolarization was antagonized by APDC. In addition, blockade of the cystine-glutamate exchange, a major nonvesicular source of extracellular glutamate, by (S)-4-carboxyphenylglycine blocked the effects induced by either APDC or APICA. However, blockade of Na+ channels by tetrodotoxin or Na+-dependent glutamate transporters bydl-threo-β-benzyloxyaspartate failed to affect the alterations in extracellular glutamate by APICA or APDC, respectively. Group II mGluRs are Gi-coupled and coperfusion with the cAMP-dependent protein kinase (PKA) activator Sp-cAMPS blocked the reduction in glutamate by APDC and the PKA inhibitor Rp-cAMPS prevented the elevation in glutamate by APICA. Taken together, these data support three conclusions: 1) group II mGluRs regulate both vesicular and nonvesicular release of glutamate in the nucleus accumbens, 2) there is tonic in vivo stimulation of mGluR2/3 by endogenous glutamate, and 3) modulation of group II mGluRs of extracellular glutamate is Ca2+- and PKA-dependent.

Footnotes

  • This research was supported in part by U.S. Public Health Service Grants MH-40817 and DA-03906.

  • Abbreviations

    mGluRs
    metabotropic glutamate receptors
    APDC
    (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate
    NAAG
    N-acetylaspartylglutamate
    2-PMPA
    2-(phosphonomethyl) pentanedioic acid
    APICA
    (RS)-amino-5-phosphonoindan-1-carboxylic acid
    (S)-4CPG
    (S)-4-carboxyphenylglycine
    TTX
    tetrodotoxin
    TBOA
    dl-threo-β-benyloxyaspartate
    Sp-/Rp-cAMPS
    Sp-/Rp-adenosine 3′5′-cyclic monophosphothioate triethylamine
    PKA
    cAMP-dependent protein kinase
    ANOVA
    analysis of variance
    PLSD
    protected least significant difference
    NAcc
    nucleus accumbens
    NMDA
    N-methyl-d-aspartate
    • Received August 2, 2001.
    • Accepted October 10, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Journal of Pharmacology and Experimental Therapeutics: 300 (1)
    Journal of Pharmacology and Experimental Therapeutics
    Vol. 300, Issue 1
    1 Jan 2002
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    Research ArticleNEUROPHARMACOLOGY

    Group II Metabotropic Glutamate Receptors Modulate Extracellular Glutamate in the Nucleus Accumbens

    Zheng-Xiong Xi, David A. Baker, Hui Shen, Daniel S. Carson and Peter W. Kalivas
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 162-171; DOI: https://doi.org/10.1124/jpet.300.1.162

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    Research ArticleNEUROPHARMACOLOGY

    Group II Metabotropic Glutamate Receptors Modulate Extracellular Glutamate in the Nucleus Accumbens

    Zheng-Xiong Xi, David A. Baker, Hui Shen, Daniel S. Carson and Peter W. Kalivas
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 162-171; DOI: https://doi.org/10.1124/jpet.300.1.162
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