The regulation of histamine release was studied on slices prepared from pieces of human cerebral cortex removed during neurosurgery and labeled with L-[3H]histidine. Depolarization by increased extracellular K+ concentration induced [3H]histamine release, although to a lesser extent than from rat brain slices. Exogenous histamine reduced by up to 60% the K+-evoked release, with an EC50 of 3.5 +/- 0.5 X 10(-8) M. The H3-receptor antagonists impromidine and thioperamide reversed the histamine effect in an apparently competitive manner and enhanced the K+-evoked release, indicating a participation of endogenous histamine in the release control process. The potencies of histamine and the H3-receptor antagonists were similar to those of these agents at presynaptic H3-autoreceptors controlling [3H]histamine release from rat brain slices. It is concluded that H3-receptors control histamine release in the human brain.