Antidepressant Treatments Change 5-HT2C Receptor mRNA Expression in Rat Prefrontal/Frontal Cortex and Hippocampus

Abstract

Background/Aims: Compelling evidence would suggest the involvement of the serotonin 2C receptor in the pathophysiology of affective disorders and in the action of antidepressants. We analyzed the time course of 5-HT2C receptor (5-HTR2C) mRNA expression during antidepressant treatment in the prefrontal/frontal cortex (P/FC) and in the hippocampus (HC) of rats chronically treated with fluoxetine (a selective serotonin reuptake inhibitor) and reboxetine (a selective noradrenaline reuptake inhibitor). We also analyzed the 5-HTR2C RNA-editing levels at the sites called A, B, C, C’ and D, which are known to modulate 5-HTR2C receptor function. Results: The expression profile of 5-HTR2C mRNA was modified during treatment with both antidepressants. In particular, we found a general down-regulation of 5-HTR2C mRNA expression in P/FC, which became significant after 3 weeks of treatment with both antidepressants and persisted after a fourth week of drug withdrawal (–46% with fluoxetine, –41% with reboxetine, p < 0.05). In HC, however, reboxetine induced significant down-regulation (–56%, p < 0.05) of 5-HTR2C mRNA after 3 weeks, while fluoxetine induced threefold up-regulation (p < 0.01) by the 2nd and 3rd week, returning to the base level after drug withdrawal of both antidepressants. Moreover, the frequency of 5-HTR2C-edited isoforms showed no significant alterations, although analysis of the RNA-editing level at the single editing sites showed small decreases in the C’ and D sites induced by reboxetine in P/FC. Conclusion: Our results suggest that chronic administration of antidepressants in rats slightly modifies the editing levels of 5-HT2C receptor but has considerable influence on its mRNA expression patterns in a way that is area- and time-specific.

Activation of serotonin2C receptors in the lateral habenular nucleus increases the expression of depression-related behaviors in the hemiparkinsonian rat

“…Thus, the 5-HT system can control the neuronal activity of the LHb by acting through 5-HT 2C receptors. Several studies have found that 5-HT 2C receptor is involved in the regulation of depression-like behaviors and a potential target for antidepressant drug development (Kennett et al, 1994;Gurevich et al, 2002;Loo et al, 2002;Seretti et al, 2004;Dremencov et al, 2005;Barbon et al, 2011). However, at present, no clear evidence Fig.…”

“…Further, activation of 5-HT 2C receptors increases neuronal excitability in several brain regions (Barnes and Sharp, 1999). In addition, several studies have also shown the involvement of 5HT 2C receptors in depression (Gurevich et al, 2002;Seretti et al, 2004;Dremencov et al, 2005;Barbon et al, 2011).…”

Mirtazapine, and mirtazapine-like compounds as possible pharmacotherapy for substance abuse disorders: Evidence from the bench and the bedside

“…The fully unedited 5-HT 2C receptor has high levels of constitutive activity (i.e., agonist-independent signaling) and strong coupling efficacy; as editing is increased, constitutive activity is diminished. Various editing patterns of the 5-HT 2C receptor are associated with depression (Gurevich et al, 2002), suicide (Gurevich et al, 2002;Niswender et al, 2001;Pandey et al, 2006;Dracheva et al, 2008b;Dracheva et al, 2008a) and schizophrenia (Sodhi et al, 2001) in humans, and these editing patterns are modulated by chronic antidepressant administration in both humans (Gurevich et al, 2002) and rodents (Barbon et al, 2011;Englander et al, 2005). It is not yet known if changes in mRNA editing of the 5-HT 2C receptor are involved in SUDs.…”

Activity Regulation of Adenosine Deaminases Acting on RNA (ADARs)

“…Therefore, these processes must be explored in great detail when investigating changes in the editing levels of ADAR targets either during development [52][53][54], under pathological conditions [55,56] and in response to specific pharmacological treatments [57][58][59][60].…”