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

Identifying the etiological factors in anxiety and depression is critical to develop more efficacious therapies. The inhibitory serotonin(1A) receptors (5-HT1AR) located on 5-HT neurons (autoreceptors) limit antidepressant responses and their expression may be increased in treatment-resistant depressed patients. 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. 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. 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. 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.