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5-HT2C receptor blockade reverses SSRI-associated basal ganglia dysfunction and potentiates therapeutic efficacy

Molecular Psychiatry volume 25, pages 3304–3321 (2020)Cite this article

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Abstract

Serotonin (5-HT) selective reuptake inhibitors (SSRIs) are widely used in the treatment of depression and anxiety disorders, but responsiveness is uncertain and side effects often lead to discontinuation. Side effect profiles suggest that SSRIs reduce dopaminergic (DAergic) activity, but specific mechanistic insight is missing. Here we show in mice that SSRIs impair motor function by acting on 5-HT2C receptors in the substantia nigra pars reticulata (SNr), which in turn inhibits nigra pars compacta (SNc) DAergic neurons. SSRI-induced motor deficits can be reversed by systemic or SNr-localized 5-HT2C receptor antagonism. SSRIs induce SNr hyperactivity and SNc hypoactivity that can also be reversed by systemic 5-HT2C receptor antagonism. Optogenetic inhibition of SNc DAergic neurons mimics the motor deficits due to chronic SSRI treatment, whereas local SNr 5-HT2C receptor antagonism or optogenetic activation of SNc DAergic neurons reverse SSRI-induced motor deficits. Lastly, we find that 5-HT2C receptor antagonism potentiates the antidepressant and anxiolytic effects of SSRIs. Together our findings demonstrate opposing roles for 5-HT2C receptors in the effects of SSRIs on motor function and affective behavior, highlighting the potential benefits of 5-HT2C receptor antagonists for both reduction of motor side effects of SSRIs and augmentation of therapeutic antidepressant and anxiolytic effects.

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Acknowledgements

This work was supported by The Sackler Institute for Developmental Psychobiology, a Sackler Award (M.S.A.), and the National Institute of Mental Health (R01 MH099118, R01 MH068073). M.S.A., E.Y.D., D.S., E.M., D.M., N.C., C.T., D.S., H.M, J.A.G., P.B., and S.R. conceived the experiments. M.S.A., E.Y.D., D.S., E.M., D.M., N.C., C.T., D.S., A.Z., M.H., J.F., S.B., and A.C. performed the experiments. M.S.A., E.Y.D., D.S. and D.M., wrote the paper. We thank Christoph Kellendonk and Eleanor Simpson for their critical review of this manuscript. Rene Hen generously contributed several 5-HT receptor deficient mouse lines for these studies. Correspondence should be addressed to Mark S. Ansorge, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NT 10032. ma2362@cumc.columbia.edu.

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  1. These authors contributed equally: Elena Y. Demireva and Deepika Suri.

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  1. Department of Psychiatry, Columbia University, New York, NY, 10032, USA

    Elena Y. Demireva, Deepika Suri, Emanuela Morelli, Darshini Mahadevia, Nao Chuhma, Catia M. Teixeira, Annette Ziolkowski, Marc Hersh, James Fifer, Sneha Bagchi, Alexei Chemiakine, Holly Moore, Jay A. Gingrich, Peter Balsam, Stephen Rayport & Mark S. Ansorge

  2. Department of Developmental Neuroscience, New York State Psychiatric Institute, New York, NY, 10032, USA

    Elena Y. Demireva, Catia M. Teixeira, Annette Ziolkowski, Jay A. Gingrich, Peter Balsam & Mark S. Ansorge

  3. Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, 10032, USA

    Nao Chuhma & Stephen Rayport

  4. Division of Systems Neuroscience, New York State Psychiatric Institute, New York, NY, 10032, USA

    Holly Moore

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Demireva, E.Y., Suri, D., Morelli, E. et al. 5-HT2C receptor blockade reverses SSRI-associated basal ganglia dysfunction and potentiates therapeutic efficacy. Mol Psychiatry 25, 3304–3321 (2020). https://doi.org/10.1038/s41380-018-0227-x

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