Research Article: Role of Serotonin via 5-HT2B Receptors in the Reinforcing Effects of MDMA in Mice

Date Published: November 23, 2009

Publisher: Public Library of Science

Author(s): Stéphane Doly, Jesus Bertran-Gonzalez, Jacques Callebert, Alexandra Bruneau, Sophie Marie Banas, Arnauld Belmer, Katia Boutourlinsky, Denis Hervé, Jean-Marie Launay, Luc Maroteaux, Kenji Hashimoto.

Abstract: The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) reverses dopamine and serotonin transporters to produce efflux of dopamine and serotonin, respectively, in regions of the brain that have been implicated in reward. However, the role of serotonin/dopamine interactions in the behavioral effects of MDMA remains unclear. We previously showed that MDMA-induced locomotion, serotonin and dopamine release are 5-HT2B receptor-dependent. The aim of the present study was to determine the contribution of serotonin and 5-HT2B receptors to the reinforcing properties of MDMA.We show here that 5-HT2B−/− mice do not exhibit behavioral sensitization or conditioned place preference following MDMA (10 mg/kg) injections. In addition, MDMA-induced reinstatement of conditioned place preference after extinction and locomotor sensitization development are each abolished by a 5-HT2B receptor antagonist (RS127445) in wild type mice. Accordingly, MDMA-induced dopamine D1 receptor-dependent phosphorylation of extracellular regulated kinase in nucleus accumbens is abolished in mice lacking functional 5-HT2B receptors. Nevertheless, high doses (30 mg/kg) of MDMA induce dopamine-dependent but serotonin and 5-HT2B receptor-independent behavioral effects.These results underpin the importance of 5-HT2B receptors in the reinforcing properties of MDMA and illustrate the importance of dose-dependent effects of MDMA on serotonin/dopamine interactions.

Partial Text: Activation of the mesolimbic dopaminergic system, which consists of projections from the midbrain ventral tegmental area (VTA) to forebrain regions, including the nucleus accumbens (NAcc), is critical for the psychostimulant and reinforcing effects of drugs of abuse [1]. Dopamine (DA) increase in the NAcc plays a critical role in reward and drug dependence and is a common response generated by all drugs of abuse [1]. On the other hand, emerging data support a role of serotonin (5-HT) in the rewarding effects of psychostimulants [2]. Serotonergic neurons from the dorsal raphé nucleus project to the VTA and the NAcc and impact dopaminergic neurotransmission [2], [3]. Thus, regulation of mesolimbic DA activity by 5-HT and its receptors plays an important role in the reinforcing effects of drugs of abuse [4], including the ‘club drug’ MDMA [5]–[8].

Sensitization is thought to underlie important aspects of vulnerability to drug addiction [28] and conditioned place preference (CPP) is a robust model used to assess the addictive properties of drugs of abuse. We show here that a “low” dose of MDMA (10 mg/kg) induces locomotor sensitization and CPP only in wildtype but not in 5-HT2B−/− mice. These findings are consistent with: 1) our microdialysis data, showing that either pharmacological inhibition or permanent ablation of 5-HT2B receptors is sufficient to block entirely both 5-HT and DA release in the NAcc following acute MDMA (10 mg/kg) injection [19], 2) lack of accumbal ERK activation in 5-HT2B−/− mice following MDMA (10 mg/kg) conditioning (Fig. 4A). Both behavioral sensitization and CPP following repeated injection of low doses (10 mg/kg) of MDMA are thus entirely 5-HT2B receptor-dependent. These data establish that 5-HT2B receptors are critical for reinforcing effects properties and establishment of long-term alterations of behavioral responses to repeated exposure to MDMA.



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