Altered 5-HT_2C receptor agonist-induced responses and 5-HT_2C receptor RNA editing in the amygdala of serotonin transporter knockout mice

Background: The serotonin 5-HT_2C receptor (5-HT_2CR) 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-HT_2C ligands. In this study, we determined the responsiveness of 5-HT_2CR 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-HT_2B/2C agonist mCPP decreased sociability and sniffing in SERT wildtype (+/+) mice, both indicative of the well-documented anxiogenic effect of mCPP. This 5-HT_2C-mediated response was absent in SERT -/- mice. Likewise, in the open field test, the selective 5-HT_2C agonist RO 60-0175 induced an anxiogenic response in SERT +/+ mice, but not in SERT -/- mice. Since 5-HT_2CR pre-mRNA is adenosine-to-inosine (A-to-I) edited, we also evaluated the 5-HT_2CR 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-HT_2C isoforms, and an increase in more edited isoforms with reduced signaling efficiency.Conclusions: These results indicate that the 5-HT_2CR in the amygdala of SERT -/- mice has increased RNA editing, which could explain, at least in part, the decreased behavioral responses to 5-HT_2C agonists in SERT -/- mice. These alterations in 5-HT_2CR in amygdala may be relevant to humans with SERT polymorphisms that alter SERT expression, function, and emotional behaviors.