Insulin regulation of dopamine transporter activity.

Abstract

A growing body of literature points to insulin as an important regulator of dopamine transporter (DAT) function. Importantly, in vitro studies suggest that insulin regulation of DAT function might be mediated by the downstream effectors phosphotidylinositol 3‐kinase (PI3K), and its downstream effector protein kinase B (PKB, or Akt), which fine tunes DAT cell surface expression. Insulin status in rats was modified by administration of the diabetogenic agent streptozotocin (STZ), food restriction and high‐fat feeding (diet induced obesity (DIO)). A battery of biochemical and molecular approaches were used to measure DAT cell surface expression and activity of insulin downstream effectors. We found that Akt activity, as well as DAT cell surface expression, was significantly reduced in hypoinsulinemic rats and DIO rats. In addition, we have looked at the specific isoform of Akt involved in this pathway. We have available to us highly specific inhibitors of Akt1 (Akti‐1), Akt2 (Akti‐2) and of both (Akti‐1/2), allowing us to determine which Akt isoform regulates DA efflux and DAT trafficking. This work looks to further define the hypothesis that insulin signaling regulates DA clearance and AMPH actions.