title: Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects.
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-HT(1A)-autoreceptors by the excess extracellular serotonin (5-HT) produced by SSRI in the raphe nuclei. Likewise, 5-HT(1A) receptor (5-HT(1A)R) gene polymorphisms leading to high 5-HT(1A)-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-HT(1A)-autoreceptor-mediated negative feedback mechanisms. We developed a conjugated siRNA (C-1A-siRNA) by covalently binding siRNA targeting 5-HT(1A) 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-HT(1A)-autoreceptor expression and suppressed 8-OH-DPAT-induced hypothermia (a pre-synaptic 5-HT(1A)R effect in mice) without affecting post-synaptic 5-HT(1A)R 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-HT(1A)R 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.
authors.affiliation: Department of Neurochemistry and Neuropharmacology, IIBB - CSIC - IDIBAPS, Barcelona, Spain. abbnqi@iibb.csic.es
authors.forename: A
authors.initials: A
authors.lastname: Bortolozzi
authors.forename: A
authors.initials: A
authors.lastname: Castañé
authors.forename: J
authors.initials: J
authors.lastname: Semakova
authors.forename: N
authors.initials: N
authors.lastname: Santana
authors.forename: G
authors.initials: G
authors.lastname: Alvarado
authors.forename: R
authors.initials: R
authors.lastname: Cortés
authors.forename: A
authors.initials: A
authors.lastname: Ferrés-Coy
authors.forename: G
authors.initials: G
authors.lastname: Fernández
authors.forename: M C
authors.initials: MC
authors.lastname: Carmona
authors.forename: M
authors.initials: M
authors.lastname: Toth
authors.forename: J C
authors.initials: JC
authors.lastname: Perales
authors.forename: A
authors.initials: A
authors.lastname: Montefeltro
authors.forename: F
authors.initials: F
authors.lastname: Artigas
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000281:Administration, Intranasal; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D017660:Autoreceptors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D004338:Drug Combinations; D015195:Drug Design; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced / Q000188:drug therapy; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D044282:Receptor, Serotonin, 5-HT1A / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D059326:Serotonergic Neurons / Q000187:drug effects / Q000378:metabolism; D020280:Sertraline / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D000928:Antidepressive Agents; D017660:Autoreceptors; D004338:Drug Combinations; D034741:RNA, Small Interfering; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D020280:Sertraline