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.
Highlights
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]
Locomotor sensitization induced with a repeated injection paradigm was abolished in 5-HT2B2/2 compared to WT mice (Fig. 1E)
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 extracellular signalregulated kinase (ERK) activation in 5-HT2B2/2 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 entirely 5-HT2B receptordependent. 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
Summary
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]. 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 [5,6,7,8]. MDMA binds to and reverses the dopamine transporter (DAT) and the serotonin transporter (SERT) to produce carrier-mediated efflux of DA and 5-HT, respectively [9]. MDMA-induced DA release in the NAcc is only partially carrier (DAT) - mediated and involves a SERTdependent 5-HT release
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