Long-term administration of imipramine caused a decrease in serotonin2 receptor binding in rat brain cerebral cortex, an effect that was abolished by ovariectomy. In contrast, ovariectomy had no effect on imipramine-induced decreases in hippocampal serotonin or in cerebral cortical and hippocampal beta-adrenergic receptor binding. Administration of estradiol or progesterone separately or in combination reestablished the effect of imipramine treatment on cortical serotonin2 receptors. These results suggest that ovarian steroids may play an important, but subtle, role in the neurochemical and perhaps clinical response to this drug.