Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro.

Stéphane Doly (1) , Emmanuel Valjent (1) , Vincent Setola (1) , Jacques Callebert (2, 3) , Denis Hervé (1) , Jean-Marie Launay (2, 3) , Luc Maroteaux (1)

1 Institut du Fer à Moulin
2 Service Biochimie et Biologie Moleculaire
3 EA3621

The "club drug" 3,4-methylenedioxymethamphetamine (MDMA; also known as ecstasy) binds preferentially to and reverses the activity of the serotonin transporter, causing release of serotonin [5-hydroxytryptamine (5-HT)] stores from nerve terminals. Subsequent activation of postsynaptic 5-HT receptors by released 5-HT has been shown to be critical for the unique psychostimulatory effects of MDMA. In contrast, the effects of direct activation of presynaptic and/or postsynaptic receptors by MDMA have received far less attention, despite the agonist actions of the drug itself at 5-HT(2) receptors, in particular the 5-HT(2B) receptor. Here we show that acute pharmacological inhibition or genetic ablation of the 5-HT(2B) receptor in mice completely abolishes MDMA-induced hyperlocomotion and 5-HT release in nucleus accumbens and ventral tegmental area. Furthermore, the 5-HT(2B) receptor dependence of MDMA-stimulated release of endogenous 5-HT from superfused midbrain synaptosomes suggests that 5-HT(2B) receptors act, unlike any other 5-HT receptor, presynaptically to affect MDMA-stimulated 5-HT release. Thus, our findings reveal a novel regulatory component in the actions of MDMA and represent the first demonstration that 5-HT(2B) receptors play an important role in the brain, i.e., modulation of 5-HT release. As such, 5-HT(2B) receptor antagonists may serve as promising therapeutic drugs for MDMA abuse.

Domaines: Biochimie, Biologie Moléculaire

Stéphane Doly, Emmanuel Valjent, Vincent Setola, Jacques Callebert, Denis Hervé, et al.. Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro.. Journal of Neuroscience, 2008, 28 (11), pp.2933-40. ⟨10.1523/JNEUROSCI.5723-07.2008⟩. ⟨inserm-00484533⟩