INHIBITION OF GLUTAMATE RELEASE - A POTENTIAL MECHANISM OF ACTION FOR THE ANTICONVULSANT U-54494A IN THE GUINEA-PIG HIPPOCAMPUS

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 AM, U-54494A significantly reduced the availability of cytosolic free calcium (Ca2+) 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 muM). 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 muM), 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 Ca2+.