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Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects

Molecular Psychiatry volume 17, pages 612–623 (2012)Cite this article

Abstract

Depression is a major health problem worldwide. Most prescribed anti-depressants, the selective serotonin reuptake inhibitors (SSRI) show limited efficacy and delayed onset of action, partly due to the activation of somatodendritic 5-HT1A-autoreceptors by the excess extracellular serotonin (5-HT) produced by SSRI in the raphe nuclei. Likewise, 5-HT1A receptor (5-HT1AR) gene polymorphisms leading to high 5-HT1A-autoreceptor expression increase depression susceptibility and decrease treatment response. In this study, we report on a new treatment strategy based on the administration of small-interfering RNA (siRNA) to acutely suppress 5-HT1A-autoreceptor-mediated negative feedback mechanisms. We developed a conjugated siRNA (C-1A-siRNA) by covalently binding siRNA targeting 5-HT1A receptor mRNA with the SSRI sertraline in order to concentrate it in serotonin axons, rich in serotonin transporter (SERT) sites. The intracerebroventricular (i.c.v.) infusion of C-1A-siRNA to mice resulted in its selective accumulation in serotonin neurons. This evoked marked anti-depressant-like effects in the forced swim and tail suspension tests, but did not affect anxiety-like behaviors in the elevated plus-maze. In parallel, C-1A-siRNA administration markedly decreased 5-HT1A-autoreceptor expression and suppressed 8-OH-DPAT-induced hypothermia (a pre-synaptic 5-HT1AR effect in mice) without affecting post-synaptic 5-HT1AR expression in hippocampus and prefrontal cortex. Moreover, i.c.v. C-1A-siRNA infusion augmented the increase in extracellular serotonin evoked by fluoxetine in prefrontal cortex to the level seen in 5-HT1AR knockout mice. Interestingly, intranasal C-1A-siRNA administration produced the same effects, thus opening the way to the therapeutic use of C-1A-siRNA. Hence, C-1A-siRNA represents a new approach to treat mood disorders as monotherapy or in combination with SSRI.

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Acknowledgements

We thank Leticia Campa for skillful work with HPLC equipment, and Verónica Paz and Noemí Jurado for technical assistance. This study was supported by grants from Spanish Ministry of Science and Innovation SAF2007-62378 and CDTI, with the participation of the DENDRIA Consortium; from Spanish Ministry of Health, Instituto de Salud Carlos III PI10/00290 and Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM; and a research contract CSIC-IDIBAPS with NEDKEN, SL-nLife Therapeutics, SL Support from the Innovative Medicines Initiative Joint Undertaking (IMI) under Grant Agreement N° 115008 (NEWMEDS) is also acknowledged. IMI is a public-private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations. AB is supported by the Research stabilization Program of the Health Department of the Generalitat de Catalunya. AM is a cofounder and board member of nLife Therapeutics, SL GA, GF and MCC are employees of nLife Therapeutics, SL.

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Author notes

  1. A Castañé and J Semakova: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurochemistry and Neuropharmacology, IIBB - CSIC - IDIBAPS, Barcelona, Spain

    A Bortolozzi, A Castañé, N Santana, R Cortés, A Ferrés-Coy & F Artigas

  2. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    A Bortolozzi & A Ferrés-Coy

  3. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain

    A Bortolozzi, A Castañé, N Santana & F Artigas

  4. Department of Physiological Sciences II, School of Medicine, Bellvitge, University of Barcelona, Barcelona, Spain

    J Semakova & J C Perales

  5. n-Life Therapeutics, S.L., La Coruña, Spain

    G Alvarado, G Fernández, M C Carmona & A Montefeltro

  6. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

    R Cortés

  7. Department of Pharmacology, Weill Medical College, Cornell University, New York, NY, USA

    M Toth

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Correspondence to A Bortolozzi or F Artigas.

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Bortolozzi, A., Castañé, A., Semakova, J. et al. Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects. Mol Psychiatry 17, 612–623 (2012). https://doi.org/10.1038/mp.2011.92

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