Acute 5-HT1A autoreceptor knockdown increases antidepressant responses and serotonin release in stressful conditions
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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.
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.
Keywords5-HT1A receptor Antidepressant effects Depression RNA interference Serotonin Stress
5-HT1AR knockout mice
Artificial cerebrospinal fluid
Dorsal raphe nucleus
Elevated plus maze
Forced swim test
Medial prefrontal cortex
Small interference RNA
Selective serotonin reuptake inhibitors
Tail suspension test
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. We gratefully acknowledge Leticia Campa for her assisting with the HPLC equipment and Verónica Paz for technical assistance.
Conflict of interest
F.A. has received consulting and educational honoraria on antidepressant drugs from Eli Lilly and Lundbeck. A.M. is a cofounder and board member of nLife Therapeutics S.L. M.C.C. is an employee on nLife Therapeutics S.L. The rest of the authors report no biomedical financial interests or potential conflicts of interest.
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