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

作者：Ferres Coy Albert; Santana Noemi; Castane Anna; Cortes Roser; Carmona Maria C; Toth Miklos; Montefeltro Andres; Artigas Francesc; Bortolozzi Anala^*

来源：Psychopharmacology, 2013, 225(1): 61-74.

DOI：10.1007/s00213-012-2795-9

• 5-HT1A receptor
• Antidepressant effects
• Depression
• RNA interference
• Serotonin
• Stress

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.

• 出版日期2013-1