Hypoinsulinemia Regulates Amphetamine-Induced Reverse Transport of Dopamine

Abstract

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.

Author Summary

Abuse of psychostimulants such as amphetamine remains a serious public health concern. Amphetamines mediate their behavioral effects by stimulating dopaminergic signaling throughout reward circuits of the brain. This property of amphetamine relies on its actions at the dopamine transporter (DAT), a presynaptic plasma membrane protein that is responsible for the reuptake of extracellular dopamine. Recently, we and others have revealed the novel ability of insulin signaling pathways in the brain to regulate DAT function as well as the cellular and behavioral actions of amphetamine. Here we used a model of Type I diabetes in rats to uncover how insulin signaling regulates DAT-mediated amphetamine effects. We show that by depleting insulin, or through selective inhibition of insulin signaling, we can severely attenuate amphetamine-induced dopamine release and impair DAT function. Our findings demonstrate in vivo the novel ability of insulin signaling to dynamically influence the neuronal effects of amphetamine-like psychostimulants. Therefore, the insulin signaling pathway, through its unique regulation of brain dopamine, may be targeted for the treatment of amphetamine abuse.

Abstract

After the striatum is exposed to amphetamines, insulin signaling regulates dopamine via downstream phosphotidylinositol 3-kinase and protein kinase B targets. This in vivo evidence points toward a mechanism for drug abuse.