We investigated the effect of cimetidine, a clinically used H2-receptor antagonist, on the induction of long-term potentiation (LTP) in the dentate gyrus of anesthetized rats. Intracerebroventricular injection of cimetidine (50-100 nmol) inhibited the induction of LTP in a dose-dependent manner. The inhibitory effect of cimetidine was not mimicked by other H2-receptor antagonists (ranitidine, famotidine) or the H1-receptor antagonist diphenhydramine or the H3-receptor antagonist thioperamide. These results suggest that cimetidine inhibits hippocampal synaptic plasticity by a novel brain mechanism unrelated to H1, H2 or H3 receptors.