Antidepressant-induced Neurogenesis is impaired in adult 5-HT2B knockout mice

DIAZ SL; DOLY S; BOUTOURLINSKY K; NARBOUX-NÊME N; MAROTEAUX L

Ginebra

Congreso; 6th FENS Forum of European Neurosciences; 2008

The Federation of European Neuroscience Societies (FENS))

The clinical effect of selective serotonin reuptake inhibitors (SSRI) antidepressants is associated with neurogenesis in the adult hippocampus. In addition, it has been demonstrated that extracellular serotonin (5-HT) levels are controlled by the 5-HT transporter, the target of SSRI. 5-HT transporter activity has been recently shown to be modulated by 5-HT2B receptors expressed in raphe neurons. Our aim was to investigate the behavioral response of 5-HT2B receptor-knockout (5-HT2BKO) mice to SSRI as well as to analyze the role of this receptor in the hippocampal neuronal proliferation and survival induced by SSRI. Behavioral responses to acute and chronic SSRI administration were evaluated by the forced swimming test and the novelty-suppressed feeding test, respectively. The response to either of these classical assays was significantly reduced in wild type mice but not in 5-HT2BKO. After a 4-week-treatment with 2 different SSRI (fluoxetine 3 mg/kg or paroxetine 2 mg/kg), immunohistochemistry of BrdU and Ki67, two markers of cell cycle progression, revealed a significant increase in cell proliferation in the subgranular zone of adult wild type mice hippocampus. On the contrary, no significant change was seen in the 5-HT2B KO mice. Additionally, we also evaluated the survival of these newborn cells by BrdU staining, after a 4- and 8- week treatment with SSRI. Similarly, survival of newborn cells was significantly higher in 8-week SSRI-treated wild type mice than KO mice. These results suggest a role of the 5-HT2B receptor in the hippocampal SSRI-induced proliferation. Previous studies from our laboratory have shown that the 5-HT2B receptor controls the production of different cytokines by fibroblasts. Therefore, the possibility that the role of the 5-HT2B receptor in the SSRI-induced neurogenesis could be mediated via the control of trophic factor such as neurotrophins will be discussed.