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Research ArticleNeuropharmacology

Selective GABA Transporter Inhibitors Tiagabine and EF1502 Exhibit Mechanistic Differences in Their Ability to Modulate the Ataxia and Anticonvulsant Action of the Extrasynaptic GABAA Receptor Agonist Gaboxadol

Karsten K. Madsen, Bjarke Ebert, Rasmus P. Clausen, Povl Krogsgaard-Larsen, Arne Schousboe and H. Steve White
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 214-219; DOI: https://doi.org/10.1124/jpet.111.179671
Karsten K. Madsen
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Bjarke Ebert
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Rasmus P. Clausen
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Povl Krogsgaard-Larsen
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Arne Schousboe
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H. Steve White
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Abstract

Modulation of the extracellular levels of GABA via inhibition of the synaptic GABA transporter GAT1 by the clinically effective and selective GAT1 inhibitor tiagabine [(R)-N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid; Gabitril] has proven to be an effective treatment strategy for focal seizures. Even though less is known about the therapeutic potential of other GABA transport inhibitors, previous investigations have demonstrated that N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (EF1502), which, like tiagabine, is inactive on GABAA receptors, inhibits both GAT1 and the extrasynaptic GABA and betaine transporter BGT1, and exerts a synergistic anticonvulsant effect when tested in combination with tiagabine. In the present study, the anticonvulsant activity and motor impairment associated with systemic administration of gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), which, at the doses used in this study (i.e., 1–5 mg/kg) selectively activates extrasynaptic α4-containing GABAA receptors, was determined alone and in combination with either tiagabine or EF1502 using Frings audiogenic seizure-susceptible and CF1 mice. EF1502, when administered in combination with gaboxadol, resulted in reduced anticonvulsant efficacy and Rotarod impairment associated with gaboxadol. In contrast, tiagabine, when administered in combination with gaboxadol, did not modify the anticonvulsant action of gaboxadol or reverse its Rotarod impairment. Taken together, these results highlight the mechanistic differences between tiagabine and EF1502 and support a functional role for BGT1 and extrasynaptic GABAA receptors.

Footnotes

  • This work was supported by the National Institutes of Health National Institutes of Neurological Disorders and Stroke [Contract N01-NS42359] (to H.S.W.); the Carlsberg Foundation [Grant 2009 01 0501] (to K.K.M.); and the Lundbeck Foundation [Grant R19-A2199] (to A.S.).

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

    doi:10.1124/jpet.111.179671.

  • ABBREVIATIONS:

    GAT1
    GABA transporter subtype 1
    GAT
    GABA transporter
    BGT1
    betaine GABA transporter 1
    GABAA-R
    GABAA receptor
    EF1502
    N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol
    LU-32-176
    N-[4,4-bis(4-fluorophenyl)-butyl]-3-hydroxy-4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol
    AGS
    audiogenic seizure
    TPE
    time-to-peak effect
    CI
    confidence interval.

  • Received January 20, 2011.
  • Accepted March 7, 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

Selective GABA Transporter Inhibitors Tiagabine and EF1502 Exhibit Mechanistic Differences in Their Ability to Modulate the Ataxia and Anticonvulsant Action of the Extrasynaptic GABAA Receptor Agonist Gaboxadol

Karsten K. Madsen, Bjarke Ebert, Rasmus P. Clausen, Povl Krogsgaard-Larsen, Arne Schousboe and H. Steve White
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 214-219; DOI: https://doi.org/10.1124/jpet.111.179671

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Research ArticleNeuropharmacology

Selective GABA Transporter Inhibitors Tiagabine and EF1502 Exhibit Mechanistic Differences in Their Ability to Modulate the Ataxia and Anticonvulsant Action of the Extrasynaptic GABAA Receptor Agonist Gaboxadol

Karsten K. Madsen, Bjarke Ebert, Rasmus P. Clausen, Povl Krogsgaard-Larsen, Arne Schousboe and H. Steve White
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 214-219; DOI: https://doi.org/10.1124/jpet.111.179671
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