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

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

Frauenchiemsee

Conferencia; Adult Neurogenesis: Structure and Function Conference; 2010

Neurogenic 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 like the 5-HT1A, 5-HT1B and 5-HT2B. In the present work, we studied whether the 5-HT2B receptor participates in the neurogenic effects of SSRI. Additionally, behavioral responses, biochemical changes and neurotrophic pathways after chronic SSRI treatment will be studied in experimental conditions where the 5-HT2B receptor is not functional. Mice invalidated for the 5-HT2B receptor (5-HT2B-/- mice) and their wild type control (WT; 129/SvPAS mice) were chronically treated with the SSRI fluoxetine at 3 mg/kg i.p. during 4 weeks. In behavioral tests after acute (forced swimming test) or chronic (novelty suppressed feeding test) SSRI treatment, WT mice respectively developed classical responses: decreased immobility time and latency to feed. However, 5-HT2B-/- mice did not respond to either behavioral test. Likewise, neurogenic effects induced by antidepressants, i.e., increase in cell proliferation and survival, were only observed in WT mice, but no response was detected in 5-HT2B-/- mice, even if basal levels were similar to those in WT animals. The increase in hipocampal 5-HT levels induced by acute SSRI was significantly higher in WT mice than in 5-HT2B-/- mice. Given that neurotrophins have been involved in the chronic effects of antidepressants, we evaluated the BDNF pathways specifically 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, and SSRI treatment did not induce any further increase. We thus, evaluated the expression of either BDNF receptors: TrkB and p75, finding similar basal levels in both genotypes. As apoptotic actions have been demonstrated for the proBDNF-p75 pathway, we analyzed the expression of some apoptotic markers in the hippocampus. 5-HT2B-/- mice showed decreased basal Bcl2 levels as well as increased expression of caspase 3, which is consistent with the observed increase in proBDNF expression. Altogether, these results confirm that the 5-HT2B receptor is implicated in the effects of SSRI. This participation appears to be as a positive autoreceptor controlling SERT activity and determining lower extracellular 5-HT availability after SSRI administration. Additionally, the increased expression of markers linked to apoptosis in 5-HT2B-/- mice suggests that the absence of neurogenic effects induced by SSRI in mice lacking the 5-HT2B receptor might be due to over-expressed apoptotic signalling. The present results support the role of the 5-HT2B receptor in the regulation of SERT activity and extend its potential as a possible target in antidepressant pharmacotherapy.