POSITIVE AUTOREGULATION OF SEROTONERGIC NEURONS BY 5-HT2B RECEPTORS

DIAZ SL; DOLY S; NARBOUX-NÊME N; FERNANDEZ SEBASTIAN; MAZOT PIERRE; BANAS S; BELMER A; ROUMIER A; MAROTEAUX L

Amsterdam

Congreso; 14th Biennial Meeting of the European Behavioural Pharmacology Society; 2011

European Behavioural Pharmacology Society

Previous findings have shown a role for 5-HT2B receptors in the behavioral and physiological effects of the SERT-targeting 5-HTreleasers, MDMA and dexfenfluramine (Banas et al., 2011, Neuropsychopharmacology 36:423?433; Doly et al., 2009, PLoS ONE 4: e7952; Doly et al., 2008, J Neurosci 28:2933?2940). Recently, it was reported that a singlenucleotide polymorphism (SNP) introducing a stop codon at the beginning of the human 5-HT2B receptor (Q20*) was associated with psychiatric diseases marked by high impulsivity in a founder population (Bevilacqua et al., 2010, Nature 468: 1061?1066). The myriad of effects induced by serotonin-selective reuptake inhibitor antidepressants (SSRI) is initially triggered by blocking the serotonin transporter (Berton et al., 2006, Nat Rev Neurosci 7:137?151) and relies on long-term adaptations of pre- and postsynaptic receptors (Popa et al., 2010, Eur J Pharmacol 628:83?90). In this context, we recently reported that the lack of 5-HT2B receptors increases the risk of  developing a serotonin syndrome (Diaz et al., 2011, Neuropharmacology, in press). We show here that behavioral and neurogenic SSRI effects are abolished after either genetic or  pharmacologic inactivation of 5-HT2B receptors. Conversely, direct stimulation of 5-HT2B receptors with an agonist induces an SSRI-like response in behavioral and neurogenic assays. Moreover, the observation that (a) this receptor is expressed by raphe serotonergic neurons, (b) the SSRI-induced increase in hippocampal serotonin concentration is strongly reduced in the absence of functional 5-HT2B receptors, and (c) a selective 5-HT2B agonist triggers an increase in raphe 5-HT levels, supports a positive regulatory function of the 5-HT2B receptor. The 5-HT2B receptor appears therefore, to positively modulate serotonergic activity and to be required for the therapeutic actions of SSRIs