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Research ArticleNeuropharmacology

Subchronic Administration and Combination Metabotropic Glutamate and GABAB Receptor Drug Therapy in Fragile X Syndrome

Laura K. K. Pacey, Sujeenthar Tharmalingam and David R. Hampson
Journal of Pharmacology and Experimental Therapeutics September 2011, 338 (3) 897-905; DOI: https://doi.org/10.1124/jpet.111.183327
Laura K. K. Pacey
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Sujeenthar Tharmalingam
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David R. Hampson
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Abstract

The most common cause of inherited mental retardation, fragile X syndrome, results from a triplet repeat expansion in the FMR1 gene and loss of the mRNA binding protein, fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group I metabotropic glutamate receptors (mGluRs) is enhanced. We previously proposed a mechanism whereby the audiogenic seizures exhibited by FMR1 null mice result from an imbalance in excitatory mGluR and inhibitory GABAB receptor (GABABR) signaling (Mol Pharmacol 76:18–24, 2009). Here, we tested the mGluR5-positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB), the mGluR5 inverse agonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), and GABAB receptor agonists, alone and in combination on receptor protein expression and audiogenic seizures in FMR1 mice. Single doses of MPEP (30 mg/kg), the GABABR orthosteric agonist R-baclofen (1 mg/kg), or the GABABR-positive allosteric modulator N,N′-dicyclopentyl-2-(methylthio)-5-nitro-4,6-pyrimidine diamine (GS-39783) (30 mg/kg), reduced the incidence of seizures. However, when administered subchronically (daily injections for 6 days), MPEP retained its anticonvulsant activity, whereas R-baclofen and GS-39783 did not. When administered at lower doses that had no effect when given alone, a single injection of MPEP plus R-baclofen also reduced seizures, but the effect was lost after subchronic administration. We were surprised to find that subchronic treatment with R-baclofen also induced tolerance to a single high dose of MPEP. These data demonstrate that tolerance develops rapidly to the antiseizure properties of R-baclofen alone and R-baclofen coadministered with MPEP, but not with MPEP alone. Our findings suggest that cross-talk between the G-protein signaling pathways of these receptors affects drug efficacy after repeated treatment.

Footnotes

  • This work was supported by the Canadian Institutes for Health Research [Grant MOP-81179]. The monoclonal anti-GABABR1 (clone NR3A/49) and GABABR2 (clone N81/2) antibodies were obtained from the University of California, Davis, CA/National Institutes of Health NeuroMab Facility, which is supported by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant U24NS050606] and maintained by the Department of Neurobiology, Physiology, and Behavior, College of Biological Sciences, University of California, Davis, CA.

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

    doi:10.1124/jpet.111.183327.

  • ABBREVIATIONS:

    FXS
    fragile X syndrome
    CDPPB
    3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide
    FMRP
    fragile X mental retardation protein
    mGluR
    metabotropic glutamate receptor
    MPEP
    2-methyl-6-(phenylethynyl)pyridine
    PND
    postnatal day
    GS-39783
    N,N′-dicyclopentyl-2-(methylthio)-5-nitro-4,6-pyrimidine diamine
    GABABR
    GABAB receptor
    CGP46381
    (3-aminopropyl)(cyclohexylmethyl)phosphinic acid
    DMSO
    dimethyl sulfoxide
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    KO
    knockout
    WT
    wild type
    PEG
    polyethylene glycol
    MTEP
    3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine.

  • Received April 25, 2011.
  • Accepted May 31, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 3
1 Sep 2011
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Research ArticleNeuropharmacology

Subchronic Administration and Combination Metabotropic Glutamate and GABAB Receptor Drug Therapy in Fragile X Syndrome

Laura K. K. Pacey, Sujeenthar Tharmalingam and David R. Hampson
Journal of Pharmacology and Experimental Therapeutics September 1, 2011, 338 (3) 897-905; DOI: https://doi.org/10.1124/jpet.111.183327

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Research ArticleNeuropharmacology

Subchronic Administration and Combination Metabotropic Glutamate and GABAB Receptor Drug Therapy in Fragile X Syndrome

Laura K. K. Pacey, Sujeenthar Tharmalingam and David R. Hampson
Journal of Pharmacology and Experimental Therapeutics September 1, 2011, 338 (3) 897-905; DOI: https://doi.org/10.1124/jpet.111.183327
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