Rescue of dopamine transporter function in hypoinsulinemic rats by a D2 receptor-ERK-dependent mechanism.

Owens WA, Williams JM, Saunders C, Avison MJ, Galli A, Daws LC
J Neurosci. 2012 32 (8): 2637-47

PMID: 22357848 · PMCID: PMC3310897 · DOI:10.1523/JNEUROSCI.3759-11.2012

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 D(2) 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 DAT function 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.

MeSH Terms (26)

Amphetamine Analysis of Variance Animals Blood Glucose Body Weight Brain Brain Mapping Corpus Striatum Diabetes Mellitus, Experimental Dopamine Dopamine Agents Dopamine Plasma Membrane Transport Proteins Drug Administration Schedule Drug Interactions Enzyme Inhibitors Hypoglycemic Agents Image Processing, Computer-Assisted Insulin Magnetic Resonance Imaging Male MAP Kinase Signaling System Oxygen Raclopride Rats Rats, Sprague-Dawley Receptors, Dopamine D2

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