Activation of the serotonin 5-HT2C receptor is involved in the enhanced anxiety in rats after single-prolonged stress

We have recently confirmed that exposure of rats to the single-prolonged stress (SPS) paradigm induces enhanced hypothalamic-pituitary-adrenal (HPA) axis negative feedback and enhanced anxiety, and found that these changes develop time-dependently following stress exposure, suggesting that it could model the neuroendocrinological and behavioral abnormalities of the post-traumatic stress disorder (PTSD) patients. In the present study, microarray analysis was performed using RNA from the hippocampus, amygdala and anterior cingulate cortex of SPS rats and unstressed controls to unveil the molecular changes underlying SPS-induced behavioral changes. Thirty-one genes were found whose time course of expression corresponded to that of behavioral changes. One gene, 5-hydroxytryptamine2C (5-HT2C) receptor, was identified as a putative candidate. The overexpression of the gene in the amygdala of SPS rats was confirmed using real-time PCR 7 days after the SPS exposure. This molecule was then pharmacologically validated using FR260010 (N-[3-(4-methyl-1H-imidazol-1-yl)phenyl]-5,6-dihydrobenzo[h]quinazolin-4-amine dimethanesulfonate), a selective 5-HT2C receptor antagonist. FR260010 (1-10 mg/kg, s.c.) significantly inhibited the enhancement of anxiety in SPS rats. These results demonstrate for the first time that activation of the brain 5-HT2C receptor is involved in the development of behavioral abnormality in this model. This suggests that selective 5-HT2C receptor antagonists might provide novel therapeutic avenues for PTSD treatment.