Journal
MOLECULAR PSYCHIATRY
Volume 17, Issue 6, Pages 612-623Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2011.92
Keywords
anti-depressant drug design; anxiety; major depression; serotonin neurons; small-interfering RNA; 5-HT1A receptors
Funding
- Spanish Ministry of Science and Innovation [SAF2007-62378]
- CDTI
- Spanish Ministry of Health
- Instituto de Salud Carlos III [PI10/00290]
- Centro de Investigacion Biomedica en Red de Salud Mental
- CIBERSAM
- CSIC-IDIBAPS
- NEDKEN
- SL-nLife Therapeutics
- Innovative Medicines Initiative Joint Undertaking (IMI)(NEWMEDS) [115008]
- Health Department of the Generalitat de Catalunya
- European Union
- European Federation of Pharmaceutical Industries and Associations
- DENDRIA Consortium
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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. Molecular Psychiatry (2012) 17, 612-623; doi:10.1038/mp.2011.92; published online 2 August 2011
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