Antidepressant treatments change 5-HT2C receptor mRNA expression in rat prefrontal/frontal cortex and hippocampus.

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.