Trace amine-associated receptor 1 is a modulator of the dopamine transporter.

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Xie Z, Miller GM

Trace amine-associated receptor 1 is a modulator of the dopamine transporter.

J Pharmacol Exp Ther. 2007 Apr;321(1):128-36. Epub 2007 Jan 18.

PubMed ID

17234899 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Amphetamine	Trace amine-associated receptor 1	Protein	Humans	Yes	Agonist	Details
Dextroamphetamine	Trace amine-associated receptor 1	Protein	Humans	Unknown	Agonist	Details
Metamfetamine	Trace amine-associated receptor 1	Protein	Humans	Yes	Agonist	Details
Propylhexedrine	Trace amine-associated receptor 1	Protein	Humans	Unknown	Agonist	Details