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

被引:108
作者
Doly, Stephane [1 ,2 ]
Valjent, Emmanuel [1 ,2 ]
Setola, Vincent [1 ,2 ]
Callebert, Jacques [3 ,4 ]
Herve, Denis [1 ,2 ]
Launay, Jean-Marie [3 ,4 ]
Maroteaux, Luc [1 ,2 ]
机构
[1] Inst Fer Moulin, INSERM, U839, F-75005 Paris, France
[2] Univ Paris 06, Inst Fer Moulin, Unite Mixte Rech S0839, F-75005 Paris, France
[3] Hop Lariboisiere, Serv Biochim, Assistance Publ Hop Paris, F-75010 Paris, France
[4] Inst Fed Rech 71, EA3261, F-75010 Paris, France
关键词
MDMA; 5-HT2B; serotonin release; microdialysis; behavior; synaptosomes;
D O I
10.1523/JNEUROSCI.5723-07.2008
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:2933 / 2940
页数:8
相关论文
共 40 条
[1]   Origin and functional role of the extracellular serotonin in the midbrain raphe nuclei [J].
Adell, A ;
Celada, P ;
Abellán, MT ;
Artigas, F .
BRAIN RESEARCH REVIEWS, 2002, 39 (2-3) :154-180
[2]   Serotonin-GABA interactions modulate MDMA-induced mesolimbic dopamine release [J].
Bankson, MG ;
Yamamoto, BK .
JOURNAL OF NEUROCHEMISTRY, 2004, 91 (04) :852-859
[3]  
Bankson MG, 2001, J PHARMACOL EXP THER, V297, P846
[4]   PHARMACOLOGIC PROFILE OF MDMA (3,4-METHYLENEDIOXYMETHAMPHETAMINE) AT VARIOUS BRAIN RECOGNITION SITES [J].
BATTAGLIA, G ;
BROOKS, BP ;
KULSAKDINUN, C ;
DESOUZA, EB .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1988, 149 (1-2) :159-163
[5]   Altered brain serotonin homeostasis and locomotor insensitivity to 3,4-methylenedioxymethamphetamine ("ecstasy") in serotonin transporter-deficient mice [J].
Bengel, D ;
Murphy, DL ;
Andrews, AM ;
Wichems, CH ;
Feltner, D ;
Heils, A ;
Mössner, R ;
Westphal, H ;
Lesch, KP .
MOLECULAR PHARMACOLOGY, 1998, 53 (04) :649-655
[6]   Regulated phosphorylation and trafficking of antidepressant-sensitive serotonin transporter proteins [J].
Blakely, RD ;
Ramamoorthy, S ;
Schroeter, S ;
Qian, Y ;
Apparsundaram, S ;
Galli, A ;
DeFelice, LJ .
BIOLOGICAL PSYCHIATRY, 1998, 44 (03) :169-178
[7]   Nuclei and subnuclei gene expression profiling in mammalian brain [J].
Bonaventure, P ;
Guo, HQ ;
Tian, B ;
Liu, XJ ;
Bittner, A ;
Roland, B ;
Salunga, R ;
Ma, XJ ;
Kamme, F ;
Meurers, B ;
Bakker, M ;
Jurzak, M ;
Leysen, JE ;
Erlander, MG .
BRAIN RESEARCH, 2002, 943 (01) :38-47
[8]   RS-127445:: a selective, high affinity, orally bioavailable 5-HT2B receptor antagonist [J].
Bonhaus, DW ;
Flippin, LA ;
Greenhouse, RJ ;
Jaime, S ;
Rocha, C ;
Dawson, M ;
Van Natta, K ;
Chang, LK ;
Pulido-Rios, T ;
Webber, A ;
Leung, E ;
Eglen, RM ;
Martin, GR .
BRITISH JOURNAL OF PHARMACOLOGY, 1999, 127 (05) :1075-1082
[9]   Evidence for a control of plasma serotonin levels by 5-hydroxytryptamine2B receptors in mice [J].
Callebert, J ;
Esteve, JM ;
Hervé, P ;
Peoc'h, K ;
Tournois, C ;
Drouet, L ;
Launay, JM ;
Maroteaux, L .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2006, 317 (02) :724-731
[10]   Immunohistochemical localisation of the serotonin 5-HT2B receptor in mouse gut, cardiovascular system, and brain [J].
Choi, DS ;
Maroteaux, L .
FEBS LETTERS, 1996, 391 (1-2) :45-51