Genetic Deletion of Trace Amine 1 Receptors Reveals Their Role in Auto-Inhibiting the Actions of Ecstasy (MDMA)
Benjamin Di Cara, Roberto Maggio, Gabriella Aloisi, Jean‐michel Rivet, Ebba Gregorsson Lundius, Takashi Yoshitake, Per Svenningsson, Mauricette Brocco, Alain P. Gobert, Lotte de Groote, Laetitia Cistarelli, Sylvie Veiga, Catherine de Montrion, Marianne Rodriguez, Jean‐pierre Galizzi, Brian Lockhart, Francis Cogé, Jean A. Boutin, Philippe Vayer, P. Monika Verdouw, Lucianne Groenink, Mark J. Millan
Journal of Neuroscience November 23, 2011 DOI: 10.1523/jneurosci.2502-11.2011 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study using genetically modified mice Peer reviewed |
|---|---|
| Population | Mice genetically deprived of trace amine-1 receptor (TA1-KO) and wild-type mice |
| Interventions | MDMA para-chloroamphetamine (PCA) haloperidol |
| Topics | MDMA Serotonin |
| Keywords | Nucleus accumbens Pharmacology Dopaminergic Receptor Agonist Striatum Adenylyl cyclase Endocrinology |
| Citations | 97 |
| Key findings | Trace amine-1 receptors inhibit MDMA-induced dopamine and serotonin release and modulate its temperature and locomotor effects. |
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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
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- Carvedilol inhibits the cardiostimulant and thermogenic effects of MDMA in humans British Journal of Pharmacology March 8, 2012
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Cites 18
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