title: Acute 5-HT₁A autoreceptor knockdown increases antidepressant responses and serotonin release in stressful conditions.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Neurochemistry and Neuropharmacology, IIBB-CSIC-IDIBAPS, C/ Roselló 161, 6th floor, 08036 Barcelona, Spain.
authors: Albert
authors: A
authors: Ferrés-Coy
authors: Noemí
authors: N
authors: Santana
authors: Anna
authors: A
authors: Castañé
authors: Roser
authors: R
authors: Cortés
authors: María C
authors: MC
authors: Carmona
authors: Miklos
authors: M
authors: Toth
authors: Andrés
authors: A
authors: Montefeltro
authors: Francesc
authors: F
authors: Artigas
authors: Analía
authors: A
authors: Bortolozzi
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000633:toxicity; D000818:Animals; D017660:Autoreceptors / Q000235:genetics; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D007035:Hypothermia / Q000139:chemically induced; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D017397:Prefrontal Cortex / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage; D011903:Raphe Nuclei; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013315:Stress, Psychological / Q000628:therapy
chemical_list: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D017660:Autoreceptors; D005473:Fluoxetine; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors