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Research ArticleNeuropharmacology

Amperometric Measurement of Glutamate Release Modulation by Gabapentin and Pregabalin in Rat Neocortical Slices: Role of Voltage-Sensitive Ca2+ α2δ-1 Subunit

Jorge E. Quintero, David J. Dooley, François Pomerleau, Peter Huettl and Greg A. Gerhardt
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 240-245; DOI: https://doi.org/10.1124/jpet.110.178384
Jorge E. Quintero
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David J. Dooley
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François Pomerleau
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Peter Huettl
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Greg A. Gerhardt
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Abstract

Gabapentin (GBP; Neurontin) and pregabalin (PGB; Lyrica, S-(+)-3-isobutylgaba) are used clinically to treat several disorders associated with excessive or inappropriate excitability, including epilepsy; pain from diabetic neuropathy, postherpetic neuralgia, and fibromyalgia; and generalized anxiety disorder. The molecular basis for these drugs' therapeutic effects are believed to involve the interaction with the auxiliary α2δ subunit of voltage-sensitive Ca2+ channel (VSCC) translating into a modulation of pathological neurotransmitter release. Glutamate as the primary excitatory neurotransmitter in the mammalian central nervous system contributes, under conditions of excessive glutamate release, to neurological and psychiatric disorders. This study used enzyme-based microelectrode arrays to directly measure extracellular glutamate release in rat neocortical slices and determine the modulation of this release by GBP and PGB. Both drugs attenuated K+-evoked glutamate release without affecting basal glutamate levels. PGB (0.1–100 μM) exhibited concentration-dependent inhibition of K+-evoked glutamate release with an IC50 value of 5.3 μM. R-(−)-3-Isobutylgaba, the enantiomer of PGB, did not significantly reduce K+-evoked glutamate release. The decrease of K+-evoked glutamate release by PGB was blocked by the l-amino acid l-isoleucine, a potential endogenous ligand of the α2δ subunit. In neocortical slices from transgenic mice having a point mutation (i.e., R217A) of the α2δ-1 (subtype) subunit of VSCC, PGB did not affect K+-evoked glutamate release yet inhibited this release in wild-type mice. The results show that GBP and PGB attenuated stimulus-evoked glutamate release in rodent neocortical slices and that the α2δ-1 subunit of VSCC appears to mediate this effect.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Aging [Grant AG00242]; and Pfizer, Inc.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.178384.

  • ABBREVIATIONS:

    GBP
    gabapentin
    PGB
    pregabalin
    VSCC
    voltage-sensitive Ca2+ channel
    MEA
    microelectrode array
    aCSF
    artificial cerebrospinal fluid
    R-IBG
    R-(−)-3-isobutylgaba.

  • Received January 11, 2011.
  • Accepted April 1, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleNeuropharmacology

Amperometric Measurement of Glutamate Release Modulation by Gabapentin and Pregabalin in Rat Neocortical Slices: Role of Voltage-Sensitive Ca2+ α2δ-1 Subunit

Jorge E. Quintero, David J. Dooley, François Pomerleau, Peter Huettl and Greg A. Gerhardt
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 240-245; DOI: https://doi.org/10.1124/jpet.110.178384

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Research ArticleNeuropharmacology

Amperometric Measurement of Glutamate Release Modulation by Gabapentin and Pregabalin in Rat Neocortical Slices: Role of Voltage-Sensitive Ca2+ α2δ-1 Subunit

Jorge E. Quintero, David J. Dooley, François Pomerleau, Peter Huettl and Greg A. Gerhardt
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 240-245; DOI: https://doi.org/10.1124/jpet.110.178384
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