The effects of iontophoretically applied histamine H2-receptor antagonists and their antagonism of various amines, acetylcholine (ACh), and adenosine 5'-monophosphate (5'-AMP) were studied on spontaneously active rat cerebral cortical neurons. Metiamide selectively blocked the depressant actions of histamine. Burimamide, in amounts necessary for histamine antagonism, also antagonized the depressant effects of noradrenaline, dopamine, and 5-hydroxytryptamine. Neither antagonist affected 5'-AMP-induced depressions, but both reduced or blocked the excitatory actions of ACh. It is concluded that metiamide may be useful as a reliable antagonist of H2 receptors on cerebral cortical neurons.