Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro.
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.
Doly
Stéphane
S
Inserm, U839 and Université Pierre et Marie Curie-Paris 6, Institut du Fer à Moulin, Unité Mixte de Recherche-S0839, Paris 75005, France.
Valjent
Emmanuel
E
Setola
Vincent
V
Callebert
Jacques
J
Hervé
Denis
D
Launay
Jean-Marie
JM
Maroteaux
Luc
L
D000818:Animals; D005260:Female; D006948:Hyperkinesis / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology* / Q000633:toxicity; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology
D044403:Receptor, Serotonin, 5-HT2B; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D012701:Serotonin; D018817:N-Methyl-3,4-methylenedioxyamphetamine