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Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response

Molecular Psychiatry volume 17, pages 926–939 (2012)Cite this article

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Abstract

High-affinity transporters for norepinephrine (NE) and serotonin (5-HT), which ensure neurotransmitter clearance at the synapse, are the principal targets of widely used antidepressant drugs. Antidepressants targeting these high-affinity transporters, however, do not provide positive treatment outcomes for all patients. Other monoamine transport systems, with lower affinity, have been detected in the brain, but their role is largely unknown. Here we report that OCT2, a member of the polyspecific organic cation transporter (OCT) family, is expressed notably in the limbic system and implicated in anxiety and depression-related behaviors in the mouse. Genetic deletion of OCT2 in mice produced a significant reduction in brain tissue concentrations of NE and 5-HT and in ex vivo uptake of both these neurotransmitters in the presence of the dual 5-HT–NE transport blocker, venlafaxine. In vivo clearance of NE and 5-HT evaluated using microiontophoretic electrophysiology was diminished in the hippocampus of OCT2−/− mice in the presence of venlafaxine, thereby affecting postsynaptic neuronal activity. OCT2−/− mice displayed an altered sensitivity to acute treatments with NE- and/or 5-HT-selective transport blockers in the forced-swim test. Moreover, the mutant mice were insensitive to long-term venlafaxine treatment in a more realistic, corticosterone-induced, chronic depression model. Our findings identify OCT2 as an important postsynaptic determinant of aminergic tonus and mood-related behaviors and a potential pharmacological target for mood disorders therapy.

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Acknowledgements

We would like to thank the anonymous reviewers for their valuable comments on the manuscript. We thank F Tronche and E Massouride for advice concerning hormonal dosage, R Schwartzmann and S Bolte at the IFR 83 Cellular Imaging platform for help with confocal microscopy, Pfizer and Lundbeck for the gift of reboxetine and citalopram, respectively, and C Betancur for critical reading of the manuscript. AB, LB and VV were recipients of fellowships from the French Ministry for Research, the Société Française de Pharmacologie et Thérapeutique and the Fondation pour la Recherche Médicale. GB was a recipient of a grant from the EGIDE foundation. Financial support was provided by the Institut National pour la Santé et la Recherche Scientifique (INSERM) and the Fondation de France.

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  1. V Vialou

    Present address: 9Present address: Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA.,

Authors and Affiliations

  1. INSERM U952, Paris, France

    A Bacq, L Balasse, F Louis, V Vialou, M-P Martres, B Giros & S Gautron

  2. CNRS UMR 7224, Paris, France

    A Bacq, L Balasse, F Louis, V Vialou, M-P Martres, B Giros & S Gautron

  3. UPMC University Paris 06, Paris, France

    A Bacq, L Balasse, F Louis, V Vialou, M-P Martres, C Chevarin, M Hamon, B Giros & S Gautron

  4. Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Lublin, Poland

    G Biala

  5. Laboratoire de Neuropharmacologie EA3544, Université Paris-Sud XI, Faculté de Pharmacie, Châtenay-Malabry, France

    B Guiard & A M Gardier

  6. Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    A Schinkel

  7. INSERM UMR 677, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, IFR 70 des Neurosciences, Paris, France

    C Chevarin & M Hamon

  8. Department of Psychiatry, Douglas Hospital, McGill University, Montreal, QC, Canada

    B Giros

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Bacq, A., Balasse, L., Biala, G. et al. Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response. Mol Psychiatry 17, 926–939 (2012). https://doi.org/10.1038/mp.2011.87

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