Acute 5-HT1A autoreceptor knockdown increases antidepressant responses and serotonin release in stressful conditions

[Rationale]: Identifying the etiological factors in anxiety and depression is critical to develop more efficacious therapies. The inhibitory serotonin1A receptors (5-HT1AR) located on 5-HT neurons (autoreceptors) limit antidepressant responses and their expression may be increased in treatment-resistant depressed patients. [Objectives]: Recently, we reported that intranasal administration of modified small interference RNA (siRNA) molecules targeting 5-HT1AR in serotonergic neurons evoked antidepressant-like effects. Here we extended this finding using marketed siRNAs against 5-HT1AR (1A-siRNA) to reduce directly the 5-HT1A autoreceptor expression and evaluate its biological consequences under basal conditions and in response to stressful situations. [Methods]: Adult mice were locally infused with vehicle, nonsense siRNA, and 1A-siRNA into dorsal raphe nucleus (DR). 5-HT1AR knockout mice (1A-KO) were also used. Histological approaches, in vivo microdialysis, and stress-related behaviors were performed to assess the effects of 5-HT1A autoreceptor knockdown. [Results]: Intra-DR 1A-siRNA infusion selectively reduced 5-HT1AR mRNA and binding levels and canceled 8-OH-DPAT-induced hypothermia. Basal extracellular 5-HT in medial prefrontal cortex (mPFC) did not differ among treatments. However, 1A-siRNA-treated mice displayed less immobility in the tail suspension and forced swim tests, as did 1A-KO mice. This was accompanied by a greater increase in prefrontal 5-HT release during tail suspension test. Moreover, intra-DR 1A-siRNA infusion augmented the increase of extracellular 5-HT in mPFC evoked by fluoxetine, up to the level in 1A-KO mice. [Conclusion]: Together with our previous report, the present results indicate that acute suppression of 5-HT1A autoreceptor expression evokes robust antidepressant-like effects, likely mediated by an increased capacity of serotonergic neurons to release 5-HT in stressful conditions.This research was supported by grants from the Spanish Ministry of Science and Innovation SAF2007-62378 (to F.A.) and CDTI, with the participation of the DENDRIA Consortium (to A.B.); from Instituto de Salud Carlos III PI10/00290 (to A.B.) and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM); and a research contract CSIC-IDIBAPS with NEDKEN, S.L.-nLife Therapeutics. Structural funds of the European Union, through the National Applied Research Projects (R+D+I 2008/11) and from the Catalan Government (grant 2009SGR220), are also acknowledged.Peer Reviewe