Regulation of the dopamine transporter: aspects relevant to psychostimulant drugs of abuse.
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.
Schmitt
Kyle C
KC
Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
Reith
Maarten E A
ME
D019969:Amphetamine-Related Disorders / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D019970:Cocaine-Related Disorders / Q000503:physiopathology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008694:Methamphetamine / Q000633:toxicity; D008959:Models, Neurological; D011493:Protein Kinase C / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D019966:Substance-Related Disorders / Q000503:physiopathology*; D054875:Ubiquitination
D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D008694:Methamphetamine; D011493:Protein Kinase C