TY - JOUR T1 - Genetic Deletion of Trace Amine 1 Receptors Reveals Their Role in Auto-Inhibiting the Actions of Ecstasy (MDMA) JF - The Journal of Neuroscience JO - J. Neurosci. SP - 16928 LP - 16940 DO - 10.1523/JNEUROSCI.2502-11.2011 VL - 31 IS - 47 AU - Benjamin Di Cara AU - Roberto Maggio AU - Gabriella Aloisi AU - Jean-Michel Rivet AU - Ebba Gregorsson Lundius AU - Takashi Yoshitake AU - Per Svenningsson AU - Mauricette Brocco AU - Alain Gobert AU - Lotte De Groote AU - Laetitia Cistarelli AU - Sylvie Veiga AU - Catherine De Montrion AU - Marianne Rodriguez AU - Jean-Pierre Galizzi AU - Brian P. Lockhart AU - Francis Cogé AU - Jean A. Boutin AU - Philippe Vayer AU - P. Monika Verdouw AU - Lucianne Groenink AU - Mark J. Millan Y1 - 2011/11/23 UR - http://www.jneurosci.org/content/31/47/16928.abstract N2 - “Ecstasy” [3,4-methylenedioxymetamphetamine (MDMA)] is of considerable interest in light of its prosocial properties and risks associated with widespread recreational use. Recently, it was found to bind trace amine-1 receptors (TA1Rs), which modulate dopaminergic transmission. Accordingly, using mice genetically deprived of TA1R (TA1-KO), we explored their significance to the actions of MDMA, which robustly activated human adenylyl cyclase-coupled TA1R transfected into HeLa cells. In wild-type (WT) mice, MDMA elicited a time-, dose-, and ambient temperature-dependent hypothermia and hyperthermia, whereas TA1-KO mice displayed hyperthermia only. MDMA-induced increases in dialysate levels of dopamine (DA) in dorsal striatum were amplified in TA1-KO mice, despite identical levels of MDMA itself. A similar facilitation of the influence of MDMA upon dopaminergic transmission was acquired in frontal cortex and nucleus accumbens, and induction of locomotion by MDMA was haloperidol-reversibly potentiated in TA1-KO versus WT mice. Conversely, genetic deletion of TA1R did not affect increases in DA levels evoked by para-chloroamphetamine (PCA), which was inactive at hTA1 sites. The TA1R agonist o-phenyl-3-iodotyramine (o-PIT) blunted the DA-releasing actions of PCA both in vivo (dialysis) and in vitro (synaptosomes) in WT but not TA1-KO animals. MDMA-elicited increases in dialysis levels of serotonin (5-HT) were likewise greater in TA1-KO versus WT mice, and 5-HT-releasing actions of PCA were blunted in vivo and in vitro by o-PIT in WT mice only. In conclusion, TA1Rs exert an inhibitory influence on both dopaminergic and serotonergic transmission, and MDMA auto-inhibits its neurochemical and functional actions by recruitment of TA1R. These observations have important implications for the effects of MDMA in humans. ER -