We examined the effect of resveratrol, a natural polyphenol, on the release of endogenous glutamate from nerve terminals purified from rat cerebral cortex. Result showed that the release of glutamate evoked by 4-aminopyridine (4-AP) was inhibited by resveratrol in a concentration-dependent manner. Further experiments reveal that resveratrol-mediated inhibition of glutamate release: (i) resulted from a reduction of vesicular exocytosis, not from an inhibition of non-vesicular release; (ii) was not due to an alternation of nerve terminal excitability; (iii) was associated with a decrease in presynaptic N- and P/Q-type voltage-dependent Ca(2+) channel activity; and (iv) appeared to involve the suppression of mitogen-activated protein (MAP) kinase pathway. These findings are the first to suggest that, in rat cerebrocortical nerve terminals, resveratrol effects a decrease in MAP kinase activation, which subsequently suppresses voltage-dependent Ca(2+) channel activity and in so doing inhibits evoked glutamate release.