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

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

Paris

Congreso; 24th ECNP Congress; 2011

European Copllege of Neuropsychopharmacology

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 SSRIs. Mice invalidated for the 5-HT2B receptor (5-HT2B-/- mice and mice treated with a 5-HT2B receptor antagonist) 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 mice with non-functional 5-HT2B receptors did not respond to either test. Likewise, antidepressant-induced neurogenic effects were only observed in WT mice. The increase in hipocampal 5-HT levels induced by acute SSRI was significantly higher in WT mice than in mice invalidated for the 5-HT2B receptor. We also demonstrated the expression of 5-HT2B receptors in raphe serotonergic neurons. We then evaluated the BDNF pathway in the hipocampus. BDNF mRNA was increased in WT mice after SSRI chronic treatment. Surprisingly, 5-HT2B-/- mice have increased basal levels of BDNF mRNA comparing to WT mice. Altogether, these results confirm that the 5-HT2B receptor is implicated in the effects of SSRIs, 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.