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Trace amine associated receptor 1 mediates methamphetamine effects on monoamine transporter function
Author(s) -
Miller Gregory M,
Xie Zhihua
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.578.5
Subject(s) - methamphetamine , monoamine neurotransmitter , chemistry , monoaminergic , pharmacology , norepinephrine transporter , dopamine transporter , serotonin transporter , meth , reuptake , serotonin , dopamine , transporter , receptor , biology , biochemistry , endocrinology , monomer , organic chemistry , acrylate , gene , polymer
Trace amine associated receptor 1 (TAAR1) is activated by a spectrum of biogenic amines, amphetamine‐like compounds and thyronamines. It is present in brain monoaminergic regions and co‐localized with the dopamine transporter (DAT) in some neurons. Here, we determined whether TAAR1 signaling in response to methamphetamine (METH) is involved in non‐competitive effects of METH on DAT, norepinephrine transporter (NET) and serotonin transporter (SERT) regulation. Uptake and efflux assays were performed in monoamine transporter/TAAR1 co‐transfected cell lines and in rhesus monkey, wild‐type (WT) and TAAR1 knockout mouse (KO) striatal ([ 3 H]DA) and [ 3 H]5‐HT) and thalamic ([ 3 H]NE) synaptosomes. METH activation of TAAR1 resulted in enhancement of uptake inhibition and promotion of efflux of [ 3 H]monoamine by DAT, NET or SERT in vitro and ex vivo, across high and low loading concentrations of [ 3 H]monoamine. At low loading concentrations (10–20 nM [ 3 H]monoamine), METH action on uptake and efflux was entirely TAAR1‐ and PKA‐/PKC‐dependent. Further experiments revealed that 1 μM METH‐induced DAT internalization was TAAR1‐ and PKC‐dependent in vitro and ex vivo. Accordingly, METH targets and interacts with TAAR1 to initiate cellular phosphorylation cascades that regulate monoamine transporter function and trafficking. Support: NIH DA022323, DA016606, DA025697, DA025802 and RR00168