Hypoinsulinemia regulates amphetamine-induced reverse transport of dopamine.

Williams JM, Owens WA, Turner GH, Saunders C, Dipace C, Blakely RD, France CP, Gore JC, Daws LC, Avison MJ, Galli A
PLoS Biol. 2007 5 (10): e274

PMID: 17941718 · PMCID: PMC2020502 · DOI:10.1371/journal.pbio.0050274

The behavioral effects of psychomotor stimulants such as amphetamine (AMPH) arise from their ability to elicit increases in extracellular dopamine (DA). These AMPH-induced increases are achieved by DA transporter (DAT)-mediated transmitter efflux. Recently, we have shown that AMPH self-administration is reduced in rats that have been depleted of insulin with the diabetogenic agent streptozotocin (STZ). In vitro studies suggest that hypoinsulinemia may regulate the actions of AMPH by inhibiting the insulin downstream effectors phosphotidylinositol 3-kinase (PI3K) and protein kinase B (PKB, or Akt), which we have previously shown are able to fine-tune DAT cell-surface expression. Here, we demonstrate that striatal Akt function, as well as DAT cell-surface expression, are significantly reduced by STZ. In addition, our data show that the release of DA, determined by high-speed chronoamperometry (HSCA) in the striatum, in response to AMPH, is severely impaired in these insulin-deficient rats. Importantly, selective inhibition of PI3K with LY294002 within the striatum results in a profound reduction in the subsequent potential for AMPH to evoke DA efflux. Consistent with our biochemical and in vivo electrochemical data, findings from functional magnetic resonance imaging experiments reveal that the ability of AMPH to elicit positive blood oxygen level-dependent signal changes in the striatum is significantly blunted in STZ-treated rats. Finally, local infusion of insulin into the striatum of STZ-treated animals significantly recovers the ability of AMPH to stimulate DA release as measured by high-speed chronoamperometry. The present studies establish that PI3K signaling regulates the neurochemical actions of AMPH-like psychomotor stimulants. These data suggest that insulin signaling pathways may represent a novel mechanism for regulating DA transmission, one which may be targeted for the treatment of AMPH abuse and potentially other dopaminergic disorders.

MeSH Terms (20)

Amphetamines Animals Antibiotics, Antineoplastic Biological Transport Central Nervous System Stimulants Corpus Striatum Dopamine Glucose Metabolism Disorders Insulin Magnetic Resonance Imaging Male Phosphatidylinositol 3-Kinases Phosphoinositide-3 Kinase Inhibitors Proto-Oncogene Proteins c-akt Rats Rats, Sprague-Dawley Signal Transduction Streptozocin Substance-Related Disorders Synaptosomes

Connections (5)

This publication is referenced by other Labnodes entities: