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Research ArticleNeuropharmacology

Inhibition of Excitatory Synaptic Transmission in Hippocampal Neurons by Levetiracetam Involves Zn2+-Dependent GABA Type A Receptor–Mediated Presynaptic Modulation

Masahito Wakita, Naoki Kotani, Kyuya Kogure and Norio Akaike
Journal of Pharmacology and Experimental Therapeutics February 2014, 348 (2) 246-259; DOI: https://doi.org/10.1124/jpet.113.208751
Masahito Wakita
Research Division for Clinical Pharmacology, Medical Corporation, Jyuryokai, Kumamoto Kinoh Hospital, Kumamoto, Japan (M.W., N.A.); Research Division for Life Science, Kumamoto Health Science University, Kumamoto, Japan (M.W., N.A.); Research Division of Neurophysiology, Kitamoto Hospital, Koshigaya, Japan (N.K., N.A); and Kogure Medical Clinic, Chouseikai Medical Corporation, Fukaya City, Saitama, Japan (K.K.)
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Naoki Kotani
Research Division for Clinical Pharmacology, Medical Corporation, Jyuryokai, Kumamoto Kinoh Hospital, Kumamoto, Japan (M.W., N.A.); Research Division for Life Science, Kumamoto Health Science University, Kumamoto, Japan (M.W., N.A.); Research Division of Neurophysiology, Kitamoto Hospital, Koshigaya, Japan (N.K., N.A); and Kogure Medical Clinic, Chouseikai Medical Corporation, Fukaya City, Saitama, Japan (K.K.)
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Kyuya Kogure
Research Division for Clinical Pharmacology, Medical Corporation, Jyuryokai, Kumamoto Kinoh Hospital, Kumamoto, Japan (M.W., N.A.); Research Division for Life Science, Kumamoto Health Science University, Kumamoto, Japan (M.W., N.A.); Research Division of Neurophysiology, Kitamoto Hospital, Koshigaya, Japan (N.K., N.A); and Kogure Medical Clinic, Chouseikai Medical Corporation, Fukaya City, Saitama, Japan (K.K.)
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Norio Akaike
Research Division for Clinical Pharmacology, Medical Corporation, Jyuryokai, Kumamoto Kinoh Hospital, Kumamoto, Japan (M.W., N.A.); Research Division for Life Science, Kumamoto Health Science University, Kumamoto, Japan (M.W., N.A.); Research Division of Neurophysiology, Kitamoto Hospital, Koshigaya, Japan (N.K., N.A); and Kogure Medical Clinic, Chouseikai Medical Corporation, Fukaya City, Saitama, Japan (K.K.)
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Abstract

Levetiracetam (LEV) is an antiepileptic drug with a unique but as yet not fully resolved mechanism of action. Therefore, by use of a simplified rat-isolated nerve-bouton preparation, we have investigated how LEV modulates glutamatergic transmission from mossy fiber terminals to hippocampal CA3 neurons. Action potential–evoked excitatory postsynaptic currents (eEPSCs) were recorded using a conventional whole-cell patch-clamp recording configuration in voltage-clamp mode. The antiepileptic drug phenytoin decreased glutamatergic eEPSCs in a concentration-dependent fashion by inhibiting voltage-dependent Na+ and Ca2+ channel currents. In contrast, LEV had no effect on eEPSCs or voltage-dependent Na+ or Ca2+ channel currents. Activation of presynaptic GABA type A (GABAA) receptors by muscimol induced presynaptic inhibition of eEPSCs, resulting from depolarization block. Low concentrations of Zn2+, which had no effect on eEPSCs, voltage-dependent Na+ or Ca2+ channel currents, or glutamate receptor–mediated whole cell currents, reduced the muscimol-induced presynaptic inhibition. LEV applied in the continuous presence of 1 µM muscimol and 1 µM Zn2+ reversed this Zn2+ modulation on eEPSCs. The antagonizing effect of LEV on Zn2+-induced presynaptic GABAA receptor inhibition was also observed with the Zn2+ chelators Ca-EDTA and RhodZin-3. Our results clearly show that LEV removes the Zn2+-induced suppression of GABAA-mediated presynaptic inhibition, resulting in a presynaptic decrease in glutamate-mediated excitatory transmission. Our results provide a novel mechanism by which LEV may inhibit neuronal activity.

Footnotes

    • Received August 13, 2013.
    • Accepted November 19, 2013.
  • M.W. and N.K, contributed equally to this work.

  • This work was supported by Otsuka Pharmaceutical Co., Ltd., and by Grants-in-Aid from Kumamoto Health Science University (to M.W. and N.A.) and by a Grant-in-Aid from Kitamoto Hospital, Koshigaya (to N.K. and N.A.).

  • dx.doi.org/10.1124/jpet.113.208751.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 348 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 348, Issue 2
1 Feb 2014
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Research ArticleNeuropharmacology

Levetiracetam and Glutamatergic Transmission

Masahito Wakita, Naoki Kotani, Kyuya Kogure and Norio Akaike
Journal of Pharmacology and Experimental Therapeutics February 1, 2014, 348 (2) 246-259; DOI: https://doi.org/10.1124/jpet.113.208751

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Research ArticleNeuropharmacology

Levetiracetam and Glutamatergic Transmission

Masahito Wakita, Naoki Kotani, Kyuya Kogure and Norio Akaike
Journal of Pharmacology and Experimental Therapeutics February 1, 2014, 348 (2) 246-259; DOI: https://doi.org/10.1124/jpet.113.208751
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