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Research ArticleNeuropharmacology

Modulation of the Antidepressant-Like Effects of Sustained Administration of Carisbamate and Lamotrigine on Monoaminergic Systems: Electrophysiological Studies in the Rat Brain

Stacey Shim, Mostafa El Mansari and Pierre Blier
Journal of Pharmacology and Experimental Therapeutics November 2013, 347 (2) 487-496; DOI: https://doi.org/10.1124/jpet.113.203315
Stacey Shim
University of Ottawa Institute of Mental Health Research (S.S., M.E.M., P.B.) and Department of Cellular and Molecular Medicine, University of Ottawa (S.S., P.B.), Ottawa, Ontario, Canada
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Mostafa El Mansari
University of Ottawa Institute of Mental Health Research (S.S., M.E.M., P.B.) and Department of Cellular and Molecular Medicine, University of Ottawa (S.S., P.B.), Ottawa, Ontario, Canada
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Pierre Blier
University of Ottawa Institute of Mental Health Research (S.S., M.E.M., P.B.) and Department of Cellular and Molecular Medicine, University of Ottawa (S.S., P.B.), Ottawa, Ontario, Canada
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Abstract

Carisbamate and lamotrigine are anticonvulsants that act on neuronal voltage-gated sodium channels. Carisbamate has shown antidepressant-like effects in animal models of depression, and lamotrigine is a mood stabilizer with a therapeutic effect in depressive episodes of patients with bipolar disorder. This study examined the effects of carisbamate and lamotrigine on monoaminergic transmission in rodents, which could contribute to their antidepressant action. In vivo electrophysiological recordings were carried out in rats after 2 and 14 days administration of vehicle, carisbamate (60 mg/kg daily), or lamotrigine (25 mg/kg daily). Overall firing activity of the dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus norepinephrine, and ventral tegmental area dopamine (DA) neurons was decreased with carisbamate. Lamotrigine also decreased 5-HT neuronal firing, and this effect was abolished by lesion of the prefrontal cortex. Despite these decreases in firing activity after their prolonged administration, both anticonvulsants exhibited a significant increase in tonic activation of hippocampus 5-HT1A receptors, as shown by a disinhibition of the firing activity of pyramidal neurons in response to the selective antagonist WAY-100635 (N-{2-[4(2-methoxyphenyl)-1-piperazinyl] ethyl}-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride). This finding reveals an increase in the 5-HT level that may be attributed to a desensitization of the terminal 5-HT1B autoreceptors. This study demonstrates that sustained carisbamate and lamotrigine administration decreases 5-HT firing in the DRN but nevertheless enhances 5-HT transmission in the forebrain. This serotonergic effect may be associated with an antiglutamatergic action and may contribute to the antidepressant-like effect of carisbamate in the forced swim test and the antidepressant properties of lamotrigine.

Footnotes

    • Received February 27, 2013.
    • Accepted August 27, 2013.
  • This work was financially supported by Ortho-McNeil Janssen Scientific Affairs, LLC (Titusville, NJ).

  • P.B. has financial involvements with Eli Lilly and Co., Labopharm, Janssen, Lundbeck, Astra-Zeneca, Pfizer, Takeda, Bristol Myers, Merck, and Servier. S.S. and M.E.M. declare no conflicts of interest.

  • dx.doi.org/10.1124/jpet.113.203315.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 347 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 347, Issue 2
1 Nov 2013
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Research ArticleNeuropharmacology

Carisbamate and Lamotrigine on Monoaminergic Neurons

Stacey Shim, Mostafa El Mansari and Pierre Blier
Journal of Pharmacology and Experimental Therapeutics November 1, 2013, 347 (2) 487-496; DOI: https://doi.org/10.1124/jpet.113.203315

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Research ArticleNeuropharmacology

Carisbamate and Lamotrigine on Monoaminergic Neurons

Stacey Shim, Mostafa El Mansari and Pierre Blier
Journal of Pharmacology and Experimental Therapeutics November 1, 2013, 347 (2) 487-496; DOI: https://doi.org/10.1124/jpet.113.203315
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