title: Altered 5-HT2C receptor agonist-induced responses and 5-HT2C receptor RNA editing in the amygdala of serotonin transporter knockout mice.
abstract: BACKGROUND
  The serotonin 5-HT2C receptor (5-HT2CR) is expressed in amygdala, a region involved in anxiety and fear responses and implicated in the pathogenesis of several psychiatric disorders such as acute anxiety and post traumatic stress disorder. In humans and in rodent models, there is evidence of both anxiogenic and anxiolytic actions of 5-HT2C ligands. In this study, we determined the responsiveness of 5-HT2CR in serotonin transporter (SERT) knockout (-/-) mice, a model characterized by increased anxiety-like and stress-responsive behaviors.
  
  
  RESULTS
  In the three-chamber social interaction test, the 5-HT2B/2C agonist mCPP decreased sociability and sniffing in SERT wildtype (+/+) mice, both indicative of the well-documented anxiogenic effect of mCPP. This 5-HT2C-mediated response was absent in SERT-/- mice. Likewise, in the open field test, the selective 5-HT2C agonist RO 60-0175 induced an anxiogenic response in SERT+/+ mice, but not in SERT-/- mice. Since 5-HT2CR pre-mRNA is adenosine-to-inosine (A-to-I) edited, we also evaluated the 5-HT2CR RNA editing profiles of SERT+/+ and SERT-/- mice in amygdala. Compared to SERT+/+ mice, SERT-/- mice showed a decrease in less edited, highly functional 5-HT2C isoforms, and an increase in more edited isoforms with reduced signaling efficiency.
  
  
  CONCLUSIONS
  These results indicate that the 5-HT2CR in the amygdala of SERT-/- mice has increased RNA editing, which could explain, at least in part, the decreased behavioral responses to 5-HT2C agonists in SERT-/- mice. These alterations in 5-HT2CR in amygdala may be relevant to humans with SERT polymorphisms that alter SERT expression, function, and emotional behaviors.
authors.affiliation: Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA. moyap@mail.nih.gov
authors.forename: Pablo R
authors.initials: PR
authors.lastname: Moya
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Fox
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Jensen
authors.forename: Justin L
authors.initials: JL
authors.lastname: Laporte
authors.forename: Helen T
authors.initials: HT
authors.lastname: French
authors.forename: Jens R
authors.initials: JR
authors.lastname: Wendland
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Murphy
mesh_terms: D000679:Amygdala / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D005021:Ethylamines / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007398:Interpersonal Relations; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010879:Piperazines / Q000494:pharmacology; D017393:RNA Editing; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D005021:Ethylamines; D007211:Indoles; D010879:Piperazines; D012322:RNA Precursors; D044405:Receptor, Serotonin, 5-HT2C; C103848:Ro 60-0175; D058826:Serotonin 5-HT2 Receptor Agonists; D050486:Serotonin Plasma Membrane Transport Proteins; C015068:1-(3-chlorophenyl)piperazine