Altered RNA editing of serotonin 2C receptor (HTR2C) has been suggested to be involved in the pathophysiology of major depression. Here we examined RNA editing status of HTR2C in the learned helplessness (LH) rats, one of well-established animal models of depression. LH rats showed the significantly increased RNA editing of site E, and tendency for increased RNA editing of other editing sites. Treatment with fluoxetine, a selective serotonin reuptake inhibitor, or imipramine, a tricyclic antidepressant, affected the RNA editing status of the LH rats. Although, these antidepressants differentially altered RNA editing status, they commonly reduced RNA editing efficiency of site E. We further revealed that altered RNA editing in the LH rats and by antidepressants was not explained by altered expression of RNA editing enzymes or their substrates (adenosine deaminases that act on RNA, HTR2C, and spliced form of HTR2C). These results suggest that alteration of RNA editing of HTR2C may play a role in the pathophysiology of depression and action of antidepressants.