QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jpet.109.153775v1 330/1/316    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Xie, Z. Articles by Miller, G. M. PubMed PubMed Citation Articles by Xie, Z. Articles by Miller, G. M.

BEHAVIORAL PHARMACOLOGY

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

Division of Neuroscience, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts

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.

Address correspondence to: Gregory M. Miller, New England Primate Research Center, Harvard Medical School, One Pine Hill Drive, Southborough, MA 01772. E-Mail: gmiller{at}hms.harvard.edu