title: Trace amine-associated receptor 1 is a modulator of the dopamine transporter.
abstract: Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor activated by a broad range of monoamines and amphetamine-related psychostimulants. Recent studies demonstrated wide distribution of TAAR1 in brain, coexpression of TAAR1 with dopamine transporter (DAT) in a subset of dopamine neurons in both mouse and rhesus monkey substantia nigra, and monoamine transporter-modulated activation. This study explored whether TAAR1 could influence DAT-mediated dopamine uptake and efflux. Rhesus monkey TAAR1 expressed with DAT in human embryonic kidney 293 cells was dose-dependently activated by dopamine or (+)-methamphetamine. This activation resulted in large cAMP increases and a transient reduction in [3H]dopamine accumulation within the cells, which was similar to the effect of dopamine D1 receptor (D1) or forskolin treatment. In addition, TAAR1 effects on dopamine uptake could be blocked by a protein kinase A or protein kinase C (PKC) inhibitor. [3H]Dopamine efflux assays performed in Dulbecco's modified Eagle's medium displayed a TAAR1-dependent spontaneous [3H]dopamine efflux that was dose-dependently augmented by dopamine or (+)-methamphetamine and that was blocked by either methylphenidate or a PKC inhibitor. DAT cells in Krebs-HEPES buffer had an apparent spontaneous [3H]dopamine loss, but it could not be blocked by either methylphenidate or a PKC inhibitor. Taken together, this study provides evidence that TAAR1 is involved in functional regulation of DAT and suggests that TAAR1 is a potentially important target for therapeutics for methamphetamine addiction.
authors.affiliation: Division of Neurochemistry, New England Primate Research Center, Harvard Medical School, One Pine Hill Drive, Southborough, MA 01772, USA.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Xie
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Miller
mesh_terms: D000818:Animals; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000502:physiology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D008253:Macaca mulatta; D008694:Methamphetamine / Q000494:pharmacology; D008774:Methylphenidate / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D013268:Stimulation, Chemical; D000095383:Trace Amine-Associated Receptors
chemical_list: D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004298:Dopamine; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D008156:Luciferases; D008694:Methamphetamine; D008774:Methylphenidate; D011493:Protein Kinase C; D011758:Pyrroles; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors; C085989:Ro 32-0432