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

MDMA (ecstasy) activates trace amine-1 receptors (TA1Rs), which normally inhibit dopamine and serotonin release. In mice lacking TA1Rs, MDMA caused only hyperthermia (not the biphasic temperature response seen in normal mice), produced larger increases in dopamine levels in the striatum, frontal cortex, and nucleus accumbens, and led to greater locomotion that was blocked by haloperidol. Serotonin release was also amplified in TA1R-deficient mice. A TA1R agonist reduced the dopamine- and serotonin-releasing effects of another drug in normal mice but not in knockout mice. TA1Rs thus limit MDMA's neurochemical and behavioral effects, suggesting they play a regulatory role in the drug's actions.

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Abstract

“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.