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Psychopharmacology

, Volume 225, Issue 1, pp 61–74 | Cite as

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

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

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.

Keywords

5-HT1A receptor Antidepressant effects Depression RNA interference Serotonin Stress 

Abbreviations

1A-KO

5-HT1AR knockout mice

5-HT

Serotonin

5-HT1AR

Serotonin1A receptors

aCSF

Artificial cerebrospinal fluid

DA

Dopamine

DR

Dorsal raphe nucleus

EPM

Elevated plus maze

FST

Forced swim test

mPFC

Medial prefrontal cortex

ns-siRNA

Nonsense siRNA

SERT

Serotonin transporter

siRNA

Small interference RNA

SSRIs

Selective serotonin reuptake inhibitors

TST

Tail suspension test

Notes

Acknowledgments

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.

Supplementary material

213_2012_2795_MOESM1_ESM.docx (2.3 mb)
ESM 1 (DOCX 2377 kb)

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Albert Ferrés-Coy
    • 1
    • 3
  • Noemí Santana
    • 1
    • 3
  • Anna Castañé
    • 1
    • 3
  • Roser Cortés
    • 1
    • 4
  • María C. Carmona
    • 5
  • Miklos Toth
    • 6
  • Andrés Montefeltro
    • 5
  • Francesc Artigas
    • 1
    • 3
  • Analía Bortolozzi
    • 1
    • 2
    • 3
  1. 1.Department of Neurochemistry and NeuropharmacologyIIBB–CSIC–IDIBAPSBarcelonaSpain
  2. 2.Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)BarcelonaSpain
  3. 3.Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)MadridSpain
  4. 4.Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)MadridSpain
  5. 5.n-Life Therapeutics, S.L.A CoruñaSpain
  6. 6.Department of Pharmacology, Weill Medical CollegeCornell UniversityNew YorkUSA

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