Role of serotonin via 5-HT2B receptors in the reinforcing effects of MDMA in mice.
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-HT(2B) receptor-dependent. The aim of the present study was to determine the contribution of serotonin and 5-HT(2B) receptors to the reinforcing properties of MDMA.We show here that 5-HT(2B) (-/-) 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-HT(2B) 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-HT(2B) receptors. Nevertheless, high doses (30 mg/kg) of MDMA induce dopamine-dependent but serotonin and 5-HT(2B) receptor-independent behavioral effects.These results underpin the importance of 5-HT(2B) receptors in the reinforcing properties of MDMA and illustrate the importance of dose-dependent effects of MDMA on serotonin/dopamine interactions.
Doly
Stéphane
S
INSERM U839, Paris, France.
Bertran-Gonzalez
Jesus
J
Callebert
Jacques
J
Bruneau
Alexandra
A
Banas
Sophie Marie
SM
Belmer
Arnauld
A
Boutourlinsky
Katia
K
Hervé
Denis
D
Launay
Jean-Marie
JM
Maroteaux
Luc
L
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D009043:Motor Activity; D009068:Movement; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D013997:Time Factors
D044403:Receptor, Serotonin, 5-HT2B; D012701:Serotonin; D048049:Extracellular Signal-Regulated MAP Kinases; D018817:N-Methyl-3,4-methylenedioxyamphetamine