Genetic Deletion of Trace Amine 1 Receptors Reveals Their Role in Auto-Inhibiting the Actions of Ecstasy (MDMA)

“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 (TA 1 Rs), which modulate dopaminergic transmission. Accordingly, using mice genetically deprived of TA 1 R ( TA 1 -KO ), we explored their significance to the actions of MDMA, which robustly activated human adenylyl cyclase-coupled TA 1 R transfected into HeLa cells. In wild-type (WT) mice, MDMA elicited a time-, dose-, and ambient temperature-dependent hypothermia and hyperthermia, whereas TA 1 -KO mice displayed hyperthermia only. MDMA-induced increases in dialysate levels of dopamine (DA) in dorsal striatum were amplified in TA 1 -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 TA 1 -KO versus WT mice. Conversely, genetic deletion of TA 1 R did not affect increases in DA levels evoked by para-chloroamphetamine (PCA), which was inactive at hTA 1 sites. The TA 1 R 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 TA 1 -KO animals. MDMA-elicited increases in dialysis levels of serotonin (5-HT) were likewise greater in TA 1 -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, TA 1 Rs exert an inhibitory influence on both dopaminergic and serotonergic transmission, and MDMA auto-inhibits its neurochemical and functional actions by recruitment of TA 1 R. These observations have important implications for the effects of MDMA in humans.