Abstract
BackgroundThe 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.ResultsIn 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.ConclusionsThese 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.
Highlights
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 serotonin transporter (SERT) +/+ mice, administration of mCPP reduced sociability, indicative of its anxiogenic effect, whereas mCPP had no effect in SERT -/- mice, reflecting a diminished responsiveness of the 5-HT2CR (Figure 1A)
MCPPtreated SERT +/+ mice spent significantly less time sniffing the stranger cage compared to vehicle-treated SERT +/+ mice, whereas mCPP was without such an effect in SERT -/- mice (Figure 1B)
Summary
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. We determined the responsiveness of 5-HT2CR in serotonin transporter (SERT) knockout (-/-) mice, a model characterized by increased anxiety-like and stress-responsive behaviors. Our previous work indicates that 5-HT transporter (SERT) knockout (-/-) mice are a valid model to study anxiety-related behaviors. These mice exhibit a complex phenotype dominated by anxiety, exaggerated stress responsiveness, and other physiological effects such as obesity and type 2 diabetes-like symptoms, all of which have been previously associated with 5-HT2CR genetic deficiencies ([9,10,11,12]; for a full review of SERT -/- mice, see [1]). The exact mechanisms responsible for the anxiety-like phenotype of SERT-/- mice are, not completely understood
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