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Europe PubMed Central
Other literature type . 2009
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Journal of Pharmacology and Experimental Therapeutics
Article . 2009 . Peer-reviewed
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A Receptor Mechanism for Methamphetamine Action in Dopamine Transporter Regulation in Brain

Authors: Xie, Zhihua; Miller, Gregory M.;

A Receptor Mechanism for Methamphetamine Action in Dopamine Transporter Regulation in Brain

Abstract

This study reveals a novel receptor mechanism for methamphetamine action in dopamine transporter (DAT) regulation. Trace amine-associated receptor 1 (TAAR1) is expressed in brain dopaminergic nuclei and is activated by methamphetamine in vitro. Here, we show that methamphetamine interaction with TAAR1 inhibits [3H]dopamine uptake, enhances or induces [3H]dopamine efflux, and triggers DAT internalization. In time course assays in which methamphetamine and [3H]dopamine were concurrently loaded into cells or synaptosomes or in pretreatment assays in which methamphetamine was washed away before [3H]dopamine loading, methamphetamine caused a distinct inhibition in [3H]dopamine uptake in TAAR1 + DAT-cotransfected cells and in wild-type mouse and rhesus monkey striatal synaptosomes. This distinct uptake inhibition was not observed in DAT-only transfected cells or in TAAR1 knockout mouse striatal synaptosomes. In [3H]dopamine efflux assays using the same cell and synaptosome preparations, methamphetamine enhanced [3H]dopamine efflux at a high loading concentration of [3H]dopamine (1 μM) or induced [3H]dopamine efflux at a low loading concentration of [3H]dopamine (10 nM) in a TAAR1-dependent manner. In DAT biotinylation assays using the same cell and synaptosome preparations, we observed that 1 μM methamphetamine induced DAT internalization in a TAAR1-dependent manner. All these TAAR1-mediated effects of methamphetamine were blocked by the protein kinase inhibitors H89 [N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline] and/or 2-{8-[(dimethylamino) methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl}-3-(1-methylindol-3-yl)maleimide (Ro32-0432), suggesting that methamphetamine interaction with TAAR1 triggers cellular phosphorylation cascades and leads to the observed effects of methamphetamine on DAT. These findings demonstrate a mediatory role of TAAR1 in methamphetamine action in DAT regulation and implicate this receptor as a potential target of therapeutics drugs for methamphetamine addiction.

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Subjects by Vocabulary

Microsoft Academic Graph classification: Dopamine Plasma Membrane Transport Proteins Pharmacology Dopamine receptor D1 Dopamine Dopamine receptor D2 TAAR1 medicine Dopamine transporter biology Chemistry Dopaminergic Methamphetamine biology.protein medicine.drug

Keywords

Dopamine, Methamphetamine, Receptors, Dopamine, Receptors, G-Protein-Coupled, Mice, Animals, Cells, Cultured, Mice, Knockout, Pharmacology, Dopamine Plasma Membrane Transport Proteins, Brain, Macaca mulatta, Behavioral Pharmacology, Molecular Medicine

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    Top 10%
    influence
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    impulse
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    Top 10%
  • citations
    This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    93
    popularity
    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 10%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    Top 10%
    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 10%
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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
93
Top 10%
Top 10%
Top 10%
Green
bronze
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