Rescue of dopamine transporter function in hypoinsulinemic rats by a D 2 receptor-ERK-dependent mechanism

Academic Article

Abstract

  • The dopamine (DA) transporter (DAT) is a major target for abused drugs and a key regulator of extracellular DA. A rapidly growing literature implicates insulin as an important regulator of DAT function. We showed previously that amphetamine (AMPH)-evoked DA release is markedly impaired in rats depleted of insulin with the diabetogenic agent streptozotocin (STZ). Similarly, functional magnetic resonance imaging experiments revealed that the blood oxygenation level-dependent signal following acute AMPH administration in STZ-treated rats is reduced. Here, we report that these deficits are restored by repeated, systemic administration of AMPH (1.78 mg/kg, every other day for 8 d). AMPH stimulates DA D 2 receptors indirectly by increasing extracellular DA. Supporting a role for D 2 receptors in mediating this "rescue," the effect was completely blocked by pre-treatment of STZ-treated rats with the D2 receptor antagonist raclopride before systemic AMPH. D 2 receptors regulate DAT cell surface expression through ERK1/2 signaling. In ex vivo striatal preparations, repeated AMPH injections increased immunoreactivity of phosphorylated ERK1/2 (p-ERK1/2) in STZ-treated but not control rats. These data suggest that repeated exposure to AMPH can rescue, by activating D 2 receptors and p-ERK signaling, deficits in DATfunction that result from hypoinsulinemia. Our data confirm the idea that disorders influencing insulin levels and/or signaling, such as diabetes and anorexia, can degrade DAT function and that insulin-independent pathways are present that may be exploited as potential therapeutic targets to restore normal DAT function. © 2012 the authors.
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Anthony Owens W; Williams JM; Saunders C; Avison MJ; Galli A; Daws LC
  • Start Page

  • 2637
  • End Page

  • 2647
  • Volume

  • 32
  • Issue

  • 8