Positive autoregulation of serotonergic neurons by 5-HT2B receptors revealed by serotonin selective antidepressants

DIAZ SL; DOLY S; NARBOUX-NÊME N; FERNANDEZ SEBASTIAN; MAZOT PIERRE; MAROTEAUX L

FLORENCIA

Congreso; 8th IBRO World Congress of Neuroscience; 2011

International Brain Research Organization (IBRO)

Chronic effects of selective serotonine reuptake inhibitors (SSRI) antidepressants are partially linked to sustained increases of serotonine (5-HT) levels, which are controlled by the 5-HT transporter (SERT). Likewise, SERT activity is regulated by different 5-HT receptors subtypes. We thus studied the putative role of 5-HT2B receptors on the chronic effects of SSRI. Mice invalidated for the 5-HT2B receptor (5-HT2B-/- mice) and their wild type (WT; 129/SvPAS mice) received SSRI during 4 weeks. In behavioral tests after acute (forced swimming test) or chronic (novelty suppressed feeding test) SSRI treatment, WT mice developed classical responses, whereas 5-HT2B-/- mice did not respond to either test. Likewise, antidepressant-induced neurogenic effects were only observed in WT mice, with no response in 5-HT2B-/- mice. The increase in hipocampal 5-HT levels induced by acute SSRI was significantly higher in WT mice than in 5-HT2B-/- mice. We also demonstrated the expression of 5-HT2B receptors in raphe serotonergic neurons. We then evaluated the BDNF pathway in the hipocampus. BDNF mRNA as well as proBDNF levels were increased in WT mice after SSRI chronic treatment. Surprisingly, 5-HT2B-/- mice have increased basal levels of BDNF mRNA and proBDNF comparing to WT mice. As apoptotic actions have been linked to the proBDNF-p75 pathway, we analyzed apoptotic markers: 5-HT2B-/- mice showed decreased basal Bcl2 levels and increased expression of caspase 3. Altogether, these results confirm that the 5-HT2B receptor is implicated in the effects of SSRI, possibly as a positive autoreceptor controlling SERT activity and determining lower extracellular 5-HT availability after SSRI administration. The present results support the potential of the 5-HT2B receptor as a possible target in antidepressant pharmacotherapy.