HIGH D-GLUCOSE CONCENTRATIONS INCREASE GABA RELEASE BUT INHIBIT RELEASE OF NOREPINEPHRINE AND 5-HYDROXYTRYPTAMINE IN RAT CEREBRAL-CORTEX

The effect of high D-glucoSe concentrations on the K+ (15-25 mM)-evoked release of [H-3]GABA, [H-3]norepinephrine ([H-3]NE), [H-3]5-hydroxytryptamine ([H-3]5-HT) and [H-3]acetylcholine ([H-3]ACh) was investigated in rat cerebral cortical slices and synaptosomes superfused with Krebs' solution which normally contains 11.1 mM glucose. In slices, the release of [H-3]GABA was enhanced by increasing D-glucose by 32-320 mM, the release of [H-3]NE and [H-3]5-HT was inhibited when D-glucose was increased by 60-320 mM but the release of [H-3]ACh was not affected. The increase of [H-3]GABA release and the inhibition of [H-3]NE release were mimicked by D-fructose and NaCl at similar osmolarities, whereas dimethylsulfoxide (DMSO; a freely membrane-permeable drug) at equimolar concentrations failed to affect the release of [H-3]GABA and [H-3]NE. The GABA(B) receptor antagonist p-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid (CGP 35348) abolished the inhibitory effect of an increase in D-glucose by 60 and 100 mM on [H-3]NE release but only tended to diminish the inhibition caused by an increase by 320 mM. In synaPtosomes, the K+-evoked release of H-3-GABA was enhanced by increasing D-glucose by 60-320 mM. The K+-evoked release of [H-3]NE was only inhibited when D-glucose was increased by 320 mM, whereas it was not affected by an increase by 100 mM. In conclusion, high D-glucose differentially influences neurotransmitter release in the brain cortex. Hyperosmolarity in the extracellular fluid together with an osmotic gradient extra- versus intracellular probably plays a role in the mechanism(s) underlying the changes observed. The inhibition of [H-3]NE release induced by an increase in D-glucose by up to 100 mM is probably due to the enhancement of[H-3]GABA release from GABAergic interneurons, thus leading to an increased activation of inhibitory GABA(B) receptors either on the noradrenergic axon terminals themselves or on an unknown excitatory neuron which innervates the noradrenergic nerve terminals. The effects of D-glucose on neurotransmitter release may contribute to the neurologic disorders during diabetic coma.