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

Francesc Artigas (1) , Analía Bortolozzi (1) , Anna Castañé (1) , Noemí Santana (1) , Roser Cortés (1) , Albert Ferrés-Coy (1) , Jana Semakova (1) , José C Perales (1) , Gabriel Alvarado (1) , Miklos Toth (1) , Geronimo Fernández (1) , María C Carmona (1) , Andrés Montefeltro (1)

1 Neurochemistry and Neuropharmacology

Depression is a major health problem worldwide. Most prescribed antidepressants, 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. Here 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 antidepressant-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 presynaptic 5-HT1AR effect in mice) without affecting postsynaptic 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.

Mots clés: 5-HT1A receptors; antidepressant drug design; anxiety; major depression; serotonin neurons

Domaines: Psychiatrie et santé mentale

Francesc Artigas, Analía Bortolozzi, Anna Castañé, Noemí Santana, Roser Cortés, et al.. Selective siRNA-mediated suppression of 5 HT1A autoreceptors evokes strong antidepressant-like effects. Molecular Psychiatry, 2011, ⟨10.1038/mp.2011.92⟩. ⟨hal-00665444⟩