CONICET | Buscador de Institutos y Recursos Humanos

Chronic effects of selective serotonin reuptake inhibitors (SSRI) antidepressants are associated to an increase in hippocampal neurogenesis possibly mediated by neurotrophins. Likewise, extracellular serotonin (5-HT) levels are controlled by the 5-HT transporter, the target of SSRIs. 5-HT transporter activity has been recently shown to be modulated by 5-HT2B receptors. Our aim was to investigate the role of 5-HT2B receptors in the effects induced by a chronic treatment with two different SSRI (fluoxetine or paroxetine). Adult male and female 5-HT2B receptor-knockout (5-HT2BKO) and their 129/SvPas control mice were employed. Behavioural tests combined with immunohistochemistry of BrdU and Ki67, two markers of cell cycle progression, and in situ hybridization of hippocampal BDNF mRNA levels were conducted in order to address the proposed objectives. The classical response to SSRIs in the novelty-suppressed feeding test was developed by wild type mice, but not by 5-HT2BKO mice. BrdU and Ki67 labeling revealed a significant increase in the hippocampal neuron proliferation and survival in wild-type mice induced after 4 and 8 week, respectively, of SSRI treatment. Nevertheless, no neurogenic effect was observed in 5-HT2BKO mice in the same conditions. In addition, we confirmed a significant increase of BDNF mRNA levels in chronically fluoxetine-treated wild type mice, but no change was seen in 5-HT2BKO mice after the SSRI treatment. Finally, the basal response of 5-HT2BKO mice in the behavioral test as well as their basal hippocampal BDNF levels were similar to those of chronically-SSRI treated wild type mice. This particularity suggests that the absence of 5-HT2B receptors induces a "depressant-resistant like" phenotype. The 5-HT2B receptors play a role in the effects of SSRI by a likely regulation of the 5-HT transporter activity. Lastly, its potential as a co-target in the treatment of depression is advocated.

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