Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro
Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro
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DOI：
10.1523/jneurosci.5723-07.2008
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发表时间：
2008-03-12
影响因子：
5.3
通讯作者：
Maroteaux, Luc
中科院分区：
文献类型：
--
作者：
Doly, Stephane;Valjent, Emmanuel;Maroteaux, Luc
“俱乐部毒品”3,4-亚甲基二氧甲基苯丙胺（MDMA，也被称为摇头丸）优先结合并逆转5-羟色胺转运体的活性，导致5-羟色胺[5-羟色胺（5-HT）]从神经末端释放出来。随后释放的5-羟色胺激活突触后5-羟色胺受体已被证明是MDMA独特的精神刺激作用的关键。相比之下，MDMA直接激活突触前和/或突触后受体的作用受到的关注要少得多，尽管药物本身对5-HT2受体，特别是5-HT2B受体具有激动剂作用。本研究表明，小鼠5-HT2B受体的急性药物抑制或基因消融完全消除mdma诱导的过度运动和伏隔核和腹侧被盖区5-HT的释放。此外，5-HT2B受体对mdma刺激的内源性5-HT释放的依赖性表明，与任何其他5-HT受体不同，5-HT2B受体在突触前影响mdma刺激的5-HT释放。因此，我们的研究结果揭示了MDMA作用中的一个新的调节成分，并首次证明了5-HT2B受体在大脑中发挥重要作用，即调节5-HT的释放。因此，5-HT2B受体拮抗剂可能成为治疗MDMA滥用的有希望的治疗药物。
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.