Rapid substrate-induced down-regulation in function and surface localization of dopamine transporters: rat dorsal striatum versus nucleus accumbens

J Neurochem. 2009 Mar;108(6):1575-84. doi: 10.1111/j.1471-4159.2009.05910.x. Epub 2009 Jan 22.


The dopamine transporter (DAT) substrates dopamine, d-amphetamine (AMPH), and methamphetamine are known to rapidly and transiently reduce DAT activity and/or surface expression in dorsal striatum and heterologous expression systems. We sought to determine if similar substrate-induced regulation of DATs occurs in rat nucleus accumbens. In dorsal striatum synaptosomes, brief (15-min) in vitro substrate pre-exposure markedly decreased maximal [(3)H]dopamine uptake velocity whereas identical substrate pre-exposure in nucleus accumbens synaptosomes produced a smaller, non-significant reduction. However, 45 min after systemic AMPH administration, maximal ex vivo [(3)H]dopamine uptake velocity was significantly reduced in both brain regions. Protein kinase C inhibition blocked AMPH's down-regulation of DAT activity. DAT synaptosomal surface expression was not modified following either the brief in vitro or in vivo AMPH pre-exposure but was reduced after a longer (1-h) in vitro pre-exposure in both brain regions. Together, our findings suggest that relatively brief substrate exposure results in greater down-regulation of DAT activity in dorsal striatum than in nucleus accumbens. Moreover, exposure to AMPH appears to regulate striatal DATs in a biphasic manner, with an initial protein kinase C-dependent decrease in DAT-mediated uptake velocity and then, with longer exposure, a reduction in DAT surface expression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amphetamine / pharmacology
  • Animals
  • Biotinylation / methods
  • Corpus Striatum / metabolism*
  • Corpus Striatum / ultrastructure
  • Dopamine / pharmacology
  • Dopamine Agents / pharmacology*
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects*
  • Enzyme Inhibitors / pharmacology
  • Indoles / pharmacology
  • Male
  • Maleimides / pharmacology
  • Methamphetamine / pharmacology
  • Nucleus Accumbens / metabolism*
  • Nucleus Accumbens / ultrastructure
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism
  • Time Factors


  • Dopamine Agents
  • Dopamine Plasma Membrane Transport Proteins
  • Enzyme Inhibitors
  • Indoles
  • Maleimides
  • Methamphetamine
  • Amphetamine
  • bisindolylmaleimide I
  • Dopamine