We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Selective siRNA-mediated suppression of 5-HT<sub>1A</sub> autoreceptors evokes strong anti-depressant-like effects.
- Authors
Bortolozzi, A; Castañé, A; Semakova, J; Santana, N; Alvarado, G; Cortés, R; Ferrés-Coy, A; Fernández, G; Carmona, M C; Toth, M; Perales, J C; Montefeltro, A; Artigas, F
- 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.
- Subjects
MENTAL depression; SEROTONIN uptake inhibitors; AUTORECEPTORS; ANTIDEPRESSANTS; GENETIC polymorphisms
- Publication
Molecular Psychiatry, 2012, Vol 17, Issue 6, p612
- ISSN
1359-4184
- Publication type
Article
- DOI
10.1038/mp.2011.92