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Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA).
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2011 Nov 23; Vol. 31 (47), pp. 16928-40. - Publication Year :
- 2011
-
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.
- Subjects :
- Animals
Dopamine physiology
Dose-Response Relationship, Drug
HeLa Cells
Humans
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Random Allocation
Receptors, G-Protein-Coupled genetics
Serotonin physiology
Gene Deletion
N-Methyl-3,4-methylenedioxyamphetamine antagonists & inhibitors
N-Methyl-3,4-methylenedioxyamphetamine pharmacology
Receptors, G-Protein-Coupled deficiency
Receptors, G-Protein-Coupled physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 31
- Issue :
- 47
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 22114263
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.2502-11.2011