Interactions between insulin and diet on striatal dopamine uptake kinetics in rodent brain slices

Abstract

Diet influences dopamine transmission in motor- and reward-related basal ganglia circuitry. In part, this reflects diet-dependent regulation of circulating and brain insulin levels. Activation of striatal insulin receptors amplifies axonal dopamine release in brain slices, and regulates food preference in vivo. The effect of insulin on dopamine release is indirect, and requires striatal cholinergic interneurons that express insulin receptors. However, insulin also acts directly on dopamine axons to increase dopamine uptake by promoting dopamine transporter (DAT) surface expression, counteracting enhanced dopamine release. Here we determined the functional consequences of acute insulin exposure and chronic diet-induced changes in insulin on DAT activity after evoked dopamine release in striatal slices from adult ad-libitum fed (AL) rats and mice, and food-restricted (FR) or high-fat/high-sugar obesogenic (OB) diet rats. Uptake kinetics were assessed by fitting evoked dopamine transients to the Michaelis-Menten equation and extracting C _peak and V _max. Insulin (30 nM) increased both parameters in the caudate putamen and nucleus accumbens core of AL rats in an insulin receptor- and PI3-kinase-dependent manner. A pure effect of insulin on uptake was unmasked using mice lacking striatal acetylcholine, in which increased V _max caused a decrease in C _peak. Diet also influenced V _max, which was lower in FR versus AL. The effects of insulin on C _peak and V _max were amplified by FR but blunted by OB, consistent with opposite consequences of these diets on insulin levels and insulin receptor sensitivity. Overall, these data reveal acute and chronic effects of insulin and diet on dopamine release and uptake that will influence brain reward pathways.

Graphical Abstract

Insulin and diet have marked effects on dopamine (DA) transmission in the brain. Insulin increases evoked striatal DA release indirectly via cholinergic interneurons (ChIs) but enhances DA transporter activity and DA uptake directly by activating insulin receptors coupled to the PI3K / Akt pathway. Food restriction (FR) or obesogenic (OB) diets that produce lower or higher plasma insulin respectively decrease DA release and uptake, relative to an ad-libitum (AL) diet. Moreover, insulin-induced increases in DA release and uptake are enhanced with FR but blunted with OB diets.