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

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

Tours

Workshop; European Behavioural and Pharmacology Society Workshop on Drugs, Psychiatric Disorders and Neurogenesis; 2010

European Behavioural and Pharmacology Society

Chronic effects of selective serotonine reuptake inhibitors (SSRI) antidepressants have been 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, but no response was detected 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 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. Additionally, the absence of neurogenic effects induced by SSRI in mice lacking the 5-HT2B receptor might be due to over-expressed apoptotic signalling. These data suggest as well, an "antidepressant-like" phenotype in 5-HT2B-/- mice which we are currently further analyzing. The present results support the potential of the 5-HT2B receptor as a possible target in antidepressant pharmacotherapy.