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

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.