Glucose modulates rat substantia nigra GABA release in vivo via ATP-sensitive potassium channels

Glucose modulates beta cell insulin secretion via effects on ATP-sensitive potassium (K_ATP) channels. To test the hypothesis that glucose exerts a similar effect on neuronal function, local glucose availability was varied in awake rats using microdialysis in the substantia nigra, the brain region with the highest density of K_ATP channels. 10 mM glucose perfusion increased GABA release by 111±42%, whereas the sulfonylurea, glipizide, increased GABA release by 84±20%. In contrast, perfusion of the K_ATP channel activator, lemakalim, or depletion of ATP by perfusion of 2-deoxyglucose with oligomycin inhibited GABA release by 44±8 and 45±11%, respectively. Moreover, the inhibition of GABA release by 2-deoxyglucose and oligomycin was blocked by glipizide. During systemic insulin-induced hypoglycemia (1.8±0.3 mM), nigral dialysate GABA concentrations decreased by 49±4% whereas levels of dopamine in striatal dialysates increased by 119±18%. We conclude that both local and systemic glucose availability influences nigral GABA release via an effect on K_ATP channels and that inhibition of GABA release may in part mediate the hyperexcitability associated with hypoglycemia. These data support the hypothesis that glucose acts as a signaling molecule, and not simply as an energy-yielding fuel, for neurons.