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Research ArticleNeuropharmacology

Acute Effects of Brexpiprazole on Serotonin, Dopamine, and Norepinephrine Systems: An In Vivo Electrophysiologic Characterization

Chris A. Oosterhof, Mostafa El Mansari and Pierre Blier
Journal of Pharmacology and Experimental Therapeutics December 2014, 351 (3) 585-595; DOI: https://doi.org/10.1124/jpet.114.218578
Chris A. Oosterhof
Institute of Mental Health Research (C.A.O., M.E.M., P.B.) and Department of Cellular and Molecular Medicine (C.A.O., P.B.), University of Ottawa, Ottawa, Ontario, Canada
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Mostafa El Mansari
Institute of Mental Health Research (C.A.O., M.E.M., P.B.) and Department of Cellular and Molecular Medicine (C.A.O., P.B.), University of Ottawa, Ottawa, Ontario, Canada
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Pierre Blier
Institute of Mental Health Research (C.A.O., M.E.M., P.B.) and Department of Cellular and Molecular Medicine (C.A.O., P.B.), University of Ottawa, Ottawa, Ontario, Canada
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Abstract

Brexpiprazole, a compound sharing structural molecular characteristics with aripiprazole, is currently under investigation for the treatment of schizophrenia and depression. Using electrophysiologic techniques, the present study assessed the in vivo action of brexpiprazole on serotonin (5-HT) receptor subtypes 5-HT1A, 5-HT1B, and 5-HT2A; dopamine (DA) D2 autoreceptors, and α1- and α2-adrenergic receptors. In addition, the effects on 5-HT1A autoreceptors in the dorsal raphe nucleus (DRN) and D2 autoreceptors in the ventral tegmental area (VTA) were compared with those of aripiprazole, an agent in wide clinical use. In the DRN, brexpiprazole completely inhibited the firing of 5-HT neurons via 5-HT1A agonism and was more potent than aripiprazole (ED50 = 230 and 700 μg/kg, respectively). In the locus coeruleus, brexpiprazole reversed the inhibitory effect of the preferential 5-HT2A receptor agonist DOI (2,5-dimethoxy-4-iodoamphetamine) on norepinephrine neuronal firing (ED50 = 110 μg/kg), demonstrating 5-HT2A antagonistic action. Brexpiprazole reversed the inhibitory effect of the DA agonist apomorphine on VTA DA neurons (ED50 = 61 μg/kg), whereas it was ineffective when administered alone, indicating partial agonistic action on D2 receptors. Compared with aripiprazole, which significantly inhibited the firing activity of VTA DA neurons, brexpiprazole displayed less efficacy at D2 receptors. In the hippocampus, brexpiprazole acted as a full agonist at 5-HT1A receptors on pyramidal neurons. Furthermore, it increased 5-HT release by terminal α2-adrenergic heteroceptor but not 5-HT1B autoreceptor antagonism. In the lateral geniculate nucleus, brexpiprazole displayed α1B-adrenoceptor antagonistic action. Taken together, these results provide insight into the in vivo action of brexpiprazole on monoamine targets relevant in the treatment of depression and schizophrenia.

Footnotes

    • Received July 24, 2014.
    • Accepted September 12, 2014.
  • This work was funded by Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan) and H. Lundbeck A/S (Valby, Denmark).

  • Some of the data in this study were presented as follows: Oosterhof CA, El Mansari M, and Blier P (2014) In vivo electrophysiological characterization of the acute effects of brexpiprazole on serotonin, dopamine, and norepinephrine neuronal activities; 69th Annual Meeting of the Society of Biological Psychiatry; 2014 May 8–10; New York, NY.

  • dx.doi.org/10.1124/jpet.114.218578.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 351 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 3
1 Dec 2014
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Research ArticleNeuropharmacology

Acute Brexpiprazole and Monoamines

Chris A. Oosterhof, Mostafa El Mansari and Pierre Blier
Journal of Pharmacology and Experimental Therapeutics December 1, 2014, 351 (3) 585-595; DOI: https://doi.org/10.1124/jpet.114.218578

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Research ArticleNeuropharmacology

Acute Brexpiprazole and Monoamines

Chris A. Oosterhof, Mostafa El Mansari and Pierre Blier
Journal of Pharmacology and Experimental Therapeutics December 1, 2014, 351 (3) 585-595; DOI: https://doi.org/10.1124/jpet.114.218578
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