title: Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA).
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.
authors: Department of Neurobiology, Institut de Recherches Servier, 78290 Croissy-sur-Seine, France.
authors: Benjamin
authors: B
authors: Di Cara
authors: Roberto
authors: R
authors: Maggio
authors: Gabriella
authors: G
authors: Aloisi
authors: Jean-Michel
authors: JM
authors: Rivet
authors: Ebba Gregorsson
authors: EG
authors: Lundius
authors: Takashi
authors: T
authors: Yoshitake
authors: Per
authors: P
authors: Svenningsson
authors: Mauricette
authors: M
authors: Brocco
authors: Alain
authors: A
authors: Gobert
authors: Lotte
authors: L
authors: De Groote
authors: Laetitia
authors: L
authors: Cistarelli
authors: Sylvie
authors: S
authors: Veiga
authors: Catherine
authors: C
authors: De Montrion
authors: Marianne
authors: M
authors: Rodriguez
authors: Jean-Pierre
authors: JP
authors: Galizzi
authors: Brian P
authors: BP
authors: Lockhart
authors: Francis
authors: F
authors: Cogé
authors: Jean A
authors: JA
authors: Boutin
authors: Philippe
authors: P
authors: Vayer
authors: P Monika
authors: PM
authors: Verdouw
authors: Lucianne
authors: L
authors: Groenink
authors: Mark J
authors: MJ
authors: Millan
mesh_terms: D000818:Animals; D004298:Dopamine / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D017353:Gene Deletion; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D011897:Random Allocation; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D012701:Serotonin / Q000502:physiology; D000095383:Trace Amine-Associated Receptors
chemical_list: D004298:Dopamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D043562:Receptors, G-Protein-Coupled; D012701:Serotonin; D000095383:Trace Amine-Associated Receptors