Serotonin 5-HT2BReceptors Are Required for 3,4-Methylenedioxymethamphetamine-Induced Hyperlocomotion and 5-HT ReleaseIn VivoandIn Vitro

The club drug MDMA (ecstasy) primarily causes serotonin release by reversing the serotonin transporter. This study in mice shows that blocking or removing the 5-HT2B receptor completely stops MDMA-induced hyperactivity and serotonin release in key brain regions (nucleus accumbens and ventral tegmental area). The 5-HT2B receptor acts presynaptically to regulate MDMA-stimulated serotonin release, a previously unknown role. These findings suggest that 5-HT2B receptor antagonists could be promising treatments for MDMA abuse.

Study at a glance

Abstract

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.