Mianserin bimodally inhibited the stimulation of cyclic AMP accumulation mediated by histamine H1- and H2-receptors in slices from guinea-pig hippocampus with Ki values of 0.003 and 4 microM, respectively. Various treatments with mianserin were undertaken to determine whether the drug significantly interacted with cerebral histamine receptors in vivo in such a way that the response of the slice preparation could be modified. In hippocampal slices from animals treated with mianserin, the H2-receptor-mediated effect was estimated by constructing concentration-response curves to impromidine, a highly selective agonist, and that mediated by H1-receptors was measured by use of 0.5 mM 2-thiazolylethylamine (a predominantly H1-receptor agonist) in the presence of a maximal concentration of impromidine. After an acute treatment (10 mg/kg), the response mediated by H1-receptors was abolished whereas the response to impromidine in increasing concentrations was unchanged. After 1 week of drug administration (10 mg/kg twice daily), a 44% reduction in the response to 2-thiazolylethylamine was observed with no change in the response mediated by H2-receptors. When a dose of mianserin equivalent to a clinical dose (1 mg/kg, twice daily) was administered for 21 days, a partial but not significant decrease of the responsiveness to the H1-receptor agonist was accompanied by a significant increase of the maximal response to impromidine. Plasma levels of mianserin were estimated by a sensitive radioreceptor assay based upon inhibition of [3H]mepyramine binding. A good correlation was found between the concentration of mianserin in plasma and the tentative estimation of an equivalent concentration of mianserin in slices.