Hypoinsulinemia regulates amphetamine-induced reverse transport of dopamine

Abstract

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.