Inhibition of glutamate release: A potential mechanism of action for the anticonvulsant U-54494A in the guinea pig hippocampus

Abstract

U-54494A, a 1,2-diamine, is a potent inhibitor of glutamate release in a synaptosomal preparation that is highly enriched with hippocampal mossy fiber (MF) nerve endings. At a concentration of 100 μM, U-54494A significantly reduced the availability of cytosolic free calcium (Ca 2+) in depolarized MF-enriched synaptosomes by 30% and inhibited the K +-evoked release of endogenous glutamate by 85%. The extent to which glutamate release was inhibited allows us to conclude that U-54494A acts directly on the MF subpopulation of glutamatergic nerve endings in the guinea pig hippocampus. In addition, this anticonvulsant effectively countered the presynaptic facilitation of K +-evoked glutamate release that is induced by kainic acid (KA). Thus, while KA (1 mM) by itself nearly doubled the rate of K +-evoked glutamate release, there was no net increase in the presence of both KA and U-54494A (100 μM). However, the opposed effects of these two compounds on glutamate release do not appear to be due to a direct interaction. In the presence of U-54494A (100 μM), KA (1 mM) significantly enhanced the K +-evoked release of glutamate. Finally, it is demonstrated that the KA-induced enhancement of glutamate release does not require the depolarization-induced entry of extracellular Ca 2+.