Regulation of the dopamine transporter: aspects relevant to psychostimulant drugs of abuse.

Abstract:

:Dopaminergic signaling in the brain is primarily modulated by dopamine transporters (DATs), which actively translocate extraneuronal dopamine back into dopaminergic neurons. Transporter proteins are highly dynamic, continuously trafficking between plasmalemmal and endosomal membranes. Changes in DAT membrane trafficking kinetics can rapidly regulate dopaminergic tone by altering the number of transporters present at the cell surface. Various psychostimulant DAT ligands-acting either as amphetamine-like substrates or cocaine-like nontranslocated inhibitors-affect transporter trafficking, triggering rapid insertion or removal of plasmalemmal DATs. In this review, we focus on the effects of psychostimulants of addiction (particularly D-methamphetamine and cocaine) on DAT regulation and membrane trafficking, with an emphasis on how these drugs may influence intracellular signaling cascades and transporter-associated scaffolding proteins to affect DAT regulation. In addition, we consider involvement of presynaptic receptors for dopamine and other ligands in DAT regulation. Finally, we discuss possible implications of transporter regulation to the putative toxicity of several substituted amphetamine derivatives commonly used as recreational drugs, as well as to the design of therapeutics for cocaine addiction.

journal_name

Ann N Y Acad Sci

authors

Schmitt KC,Reith ME

doi

10.1111/j.1749-6632.2009.05148.x

subject

Has Abstract

pub_date

2010-02-01 00:00:00

pages

316-40

eissn

0077-8923

issn

1749-6632

pii

NYAS5148

journal_volume

1187

pub_type

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