High d-glucose concentrations increase GABA release but inhibit release of norepinephrine and 5-hydroxytryptamine in rat cerebral cortex

Abstract

The effect of high d-glucose concentrations on the K + (15–25 mM)-evoked release of [ 3H]GABA, [ 3H]norepinephrine ([ 3H]NE), [ 3H]5-hydroxytryptamine ([ 3H]5-HT) and [ 3H]acetylcholine ([ 3H]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 [ 3H]GABA was enhanced by increasing d-glucose by 32–320 mM, the release of [ 3H]NE and [ 3H]5-HT was inhibited when d-glucose was increased by 60–320 mM but the release of [ 3H]ACh was not affected. The increase of [ 3H]GABA release and the inhibition of [ 3H]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 [ 3H]GABA and [ 3H]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 [ 3H]NE release but only tended to diminish the inhibition caused by an increase by 320 mM. In synaptosomes, the K +-evoked release of 3H-GABA was enhanced by increasing d-glucose by 60–320 mM. The K +-evoked release of [ 3H]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 [ 3H]NE release induced by an increase in d-glucose by up to 100 mM is probably due to the enhancement of [ 3H]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.