The chronic administration of mianserin for 14 days leads to a marked decrease in the maximal number of serotonin2 (5-HT2) binding sites in brains of rats and mice with no change in the KD values. The decrease in [3H]spiroperidol binding to the 5-HT2 site in rats was most pronounced in the frontal cortex with only minor changes in hippocampus and pons-medulla. The 5-HT1 site was largely unaffected. The decrease in the Bmax for 5-HT2 site also occurred after a single dose of mianserin, although mianserin was more potent when given chronically. Maximal inhibition of binding occurred with a chronic dose of 0.5 mg/kg. The greatest decrease was found 48 hr after single or repeated doses with a gradual return to normal levels within 10 days. The administration of mianserin also leads to a decrease in 5-methoxy-N,N-dimethyltryptamine-induced head twitches in mice assayed 48 and 96 hr after a single or repeated doses, which is presumably correlated with the decrease in the 5-HT2 binding site assayed in vitro.