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The Journal of Neuroscience, March 12, 2008, 28(11):2933-2940; doi:10.1523/JNEUROSCI.5723-07.2008

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Behavioral/Systems/Cognitive
Serotonin 5-HT2B Receptors Are Required for 3,4-Methylenedioxymethamphetamine-Induced Hyperlocomotion and 5-HT Release In Vivo and In Vitro

Stéphane Doly,1,2 Emmanuel Valjent,1,2 Vincent Setola,1,2 Jacques Callebert,3,4 Denis Hervé,1,2 Jean-Marie Launay,3,4 and Luc Maroteaux1,2

1Inserm, U839 and 2Université Pierre et Marie Curie-Paris 6, Institut du Fer à Moulin, Unité Mixte de Recherche-S0839, Paris 75005, France, and 3Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Service de Biochimie and 4EA3621, Institut Fédératif de Recherche 71, Paris 75010, France

Correspondence should be addressed to Luc Maroteaux, Inserm, U839, Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France. Email: luc.maroteaux{at}chups.jussieu.fr

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-HT2 receptors, in particular the 5-HT2B receptor. Here we show that acute pharmacological inhibition or genetic ablation of the 5-HT2B receptor in mice completely abolishes MDMA-induced hyperlocomotion and 5-HT release in nucleus accumbens and ventral tegmental area. Furthermore, the 5-HT2B receptor dependence of MDMA-stimulated release of endogenous 5-HT from superfused midbrain synaptosomes suggests that 5-HT2B 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-HT2B receptors play an important role in the brain, i.e., modulation of 5-HT release. As such, 5-HT2B receptor antagonists may serve as promising therapeutic drugs for MDMA abuse.

Key words: MDMA; 5-HT2B; serotonin release; microdialysis; behavior; synaptosomes

Received Nov. 12, 2007; revised Jan. 21, 2008; accepted Jan. 21, 2008.

Correspondence should be addressed to Luc Maroteaux, Inserm, U839, Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France. Email: luc.maroteaux{at}chups.jussieu.fr






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