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

AuthorsFerrés-Coy, Albert ; Santana, Noemí ; Castañé, Anna ; Cortés, Roser ; Artigas, Francesc ; Bortolozzi, Analía
Issue Date2013
CitationPsychopharmacology 225(1): 61-74 (2013)
Abstract[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.
Publisher version (URL)http://dx.doi.org/10.1007/s00213-012-2795-9
Identifiersdoi: 10.1007/s00213-012-2795-9
issn: 0033-3158
e-issn: 1432-2072
Appears in Collections:(IIBB) Artículos
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