Journal Article

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

Cortés, Roser, Castañé, Anna, Artigas, Francesc, Carmona, María C., Toth, Miklos, Montefeltro, Andrés, Ferrés-Coy, Albert, Bortolozzi, Analía, Santana, Noemí

2013

Overview

Rationale Identifying the etiological factors in anxiety and depression is critical to develop more efficacious therapies. The inhibitory serotonin 1A receptors (5-HT 1A R) 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-HT 1A R in serotonergic neurons evoked antidepressant-like effects. Here we extended this finding using marketed siRNAs against 5-HT 1A R (1A-siRNA) to reduce directly the 5-HT 1A 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-HT 1A R knockout mice (1A-KO) were also used. Histological approaches, in vivo microdialysis, and stress-related behaviors were performed to assess the effects of 5-HT 1A autoreceptor knockdown. Results Intra-DR 1A-siRNA infusion selectively reduced 5-HT 1A R 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-HT 1A autoreceptor expression evokes robust antidepressant-like effects, likely mediated by an increased capacity of serotonergic neurons to release 5-HT in stressful conditions.

• Publisher: Springer-Verlag
• Subject: 8-Hydroxy-2-(di-n-propylamino)tetralin - toxicity / Animals / Autoreceptors - genetics / Behavior, Animal - drug effects / Biomedical and Life Sciences / Biomedicine / Disease Models, Animal / Fluoxetine - pharmacology / Gene Knockdown Techniques / Hypothermia - chemically induced / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Microdialysis / Neurosciences / Original Investigation / Pharmacology/Toxicology / Prefrontal Cortex - metabolism / Psychiatry / Raphe Nuclei / Receptor, Serotonin, 5-HT1A - genetics / RNA, Messenger - metabolism / RNA, Small Interfering - administration & dosage / Serotonin - metabolism / Serotonin Uptake Inhibitors - pharmacology / Stress, Psychological - therapy