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

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.

Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype

“…It is noteworthy that 5-HT 2B receptors have been shown to modulate aspects of both serotonergic and dopaminergic neurotransmission (Bevilacqua et al, 2010;Diaz and Maroteaux, 2011;Doly et al, 2008). In particular, ex vivo studies have indicated that 5-HT 2B receptors may serve as positive autoregulator of the serotonergic tone through modulating the 5-HT transporter (SERT) in raphe neurons (Launay et al, 2006), and in vivo studies in mice further confirmed that 5-HT 2B receptors contribute to the behavioral effects of the SERT-targeting 5-HT releasers, MDMA (ie, ecstasy) and dexfenfluramine (Banas et al, 2011;Doly et al, 2009;Doly et al, 2008). Recently, Auclair et al (2010) reported that 5-HT 2B receptors control the mesoaccumbal DA pathway activity, as an acute systemic administration of the 5-HT 2B subtype-selective antagonist RS127445 in rats induced a region-selective reduction of extracellular DA levels in the NAC in response to amphetamine challenge.…”

Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain

“…Male Sprague-Dawley rats (Janvier, and a selectivity for this receptor 1,000 times stronger than that for other receptors and monoamine uptake sites [12,19,20]. A 1 mg/ml stock solution of RS127445 was prepared in DMSO.…”

Role of the N-Terminal Region in G Protein–Coupled Receptor Functions: Negative Modulation Revealed by 5-HT2BReceptor Polymorphisms

“…Understanding the genetic bases of drug abuse vulnerability and particular allelic variants that contribute to this vulnerability can strongly improve our understanding of human addictions. We have recently extended the role of serotonin (5-HT) in the behavioral responses to psychostimulants by revealing that the genetic ablation of Htr 2B in mice, the gene encoding 5-HT 2B receptors, eliminates locomotor response and place preference induced by MDMA [(6)-3,4-methylenedioxymethamphetamine] (Doly et al, 2008(Doly et al, , 2009). Independently, three novel single nucleotide polymorphisms, two of which result in a point mutation, were described in a drug-abusing population (Lin et al, 2004).…”