Role of 5-HT2B receptor in the neurogenic effects induced by SSRI antidepressants

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

Chicago

Congreso; 39th Annual Meeting of the Society for Neuroscience; 2009

Society for Neuroscience

Classically, clinical effects of antidepressants are observed only after a couple of week of administration. This delay has been linked to the time required for antidepressant-dependent neurogenic effect, a process where neurotrophins appear to be involved. Likewise, the serotonin (5-HT) transporter, which is the target of selective serotonin reuptake inhibitors (SSRI), can be regulated by certain 5-HT receptors, including the 5-HT2B receptor. After having observed that 5-HT2B receptors are necessary for the acute behavioral responses to SSRIs, we studied the putative participation of this receptor in SSRI chronic effects. Adult male and female 5-HT2B receptor-knockout (5-HT2BKO) and their 129/SvPas control mice were employed. Behavioral tests combined with immunohistochemistry of cell cycle markers as well as BDNF expression studies were conducted in order to address the proposed objective. The classical response to the chronic SSRI treatment in the novelty-suppressed feeding test was observed in wild type mice, but not in 5-HT2BKO mice. BrdU staining revealed a significant increase in the hippocampal neuron proliferation and survival in wild-type mice after 4 and 8 weeks, respectively, of SSRI treatment. Nevertheless, no neurogenic effect was observed in 5-HT2BKO mice in the same experimental conditions. In addition, we confirmed a significant increase of BDNF mRNA and protein levels in hippocampus of chronically SSRI-treated wild type mice, but no change was seen in 5-HT2BKO mice. Finally, the basal response of 5-HT2BKO mice in the novelty-suppressed feeding test and their basal hippocampal BDNF levels were similar to those of chronically-SSRI treated wild type mice. This particularity suggests that the genetic ablation of 5-HT2B receptors induces an "antidepressant-like" phenotype. In conclusion, 5-HT2B receptors participate in the effects of SSRIs by regulating 5-HT transporter activity. Lastly, its potential as a co-target in the treatment of depression is advocated.