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5-HT2B receptors are required for serotonin-selective antidepressant actions

Molecular Psychiatry volume 17, pages 154–163 (2012)Cite this article

Abstract

The therapeutic effects induced by serotonin-selective reuptake inhibitor (SSRI) antidepressants are initially triggered by blocking the serotonin transporter and rely on long-term adaptations of pre- and post-synaptic receptors. We show here that long-term behavioral and neurogenic SSRI effects are abolished after either genetic or pharmacological inactivation of 5-HT2B receptors. Conversely, direct agonist stimulation of 5-HT2B receptors induces an SSRI-like response in behavioral and neurogenic assays. Moreover, the observation that (i) this receptor is expressed by raphe serotonergic neurons, (ii) the SSRI-induced increase in hippocampal extracellular serotonin concentration is strongly reduced in the absence of functional 5-HT2B receptors and (iii) a selective 5-HT2B agonist mimics SSRI responses, supports a positive regulation of serotonergic neurons by 5-HT2B receptors. The 5-HT2B receptor appears, therefore, to positively modulate serotonergic activity and to be required for the therapeutic actions of SSRIs. Consequently, the 5-HT2B receptor should be considered as a new tractable target in the combat against depression.

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Acknowledgements

We thank Drs Patricia Gaspar and Fiona Francis for critical reading of the manuscript, Sarah Rogan for English editing of the manuscript, as well as C G Bonelli (Institute of Pharmacological Research-CONICET, Argentina) for her excellent assistance on HPLC techniques. Pet-1-CRE and Pet-1−/− mice were kindly provided by Dr Evan Deneris (Case Western Reserve University, Cleveland, USA), whereas RCE:loxP mice were kindly obtained from Dr Fishell (Smilow Research Center, New York University, USA). This work has been supported by funds from the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Université Pierre et Marie Curie, and by grants from the Fondation de France, the Fondation pour la Recherche Médicale, the French ministry of research (Agence Nationale pour la Recherche), and the European Commission (FP7-health-2007-A-201714-DEVANX). S Diaz is supported by fellowships from IBRO and from Region Ile de France DIM STEM and S Doly by a LeFoulon-DeLalande fellowship.

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Authors and Affiliations

  1. UMR-S839 INSERM, Paris, France

    S L Diaz, S Doly, N Narboux-Nême, S Fernández, P Mazot, S M Banas, K Boutourlinsky, I Moutkine, A Belmer, A Roumier & L Maroteaux

  2. Université Pierre et Marie Curie, Paris, France

    S L Diaz, S Doly, N Narboux-Nême, S Fernández, P Mazot, S M Banas, K Boutourlinsky, I Moutkine, A Belmer, A Roumier & L Maroteaux

  3. Institut du Fer à Moulin, Paris, France

    S L Diaz, S Doly, N Narboux-Nême, S Fernández, P Mazot, S M Banas, K Boutourlinsky, I Moutkine, A Belmer, A Roumier & L Maroteaux

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Correspondence to L Maroteaux.

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Diaz, S., Doly, S., Narboux-Nême, N. et al. 5-HT2B receptors are required for serotonin-selective antidepressant actions. Mol Psychiatry 17, 154–163 (2012). https://doi.org/10.1038/mp.2011.159

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