Long term (21-day) treatment with antidepressants induces a decrease in beta-adrenergic and serotonin 2 (5-HT2) receptor binding in rat brain frontal cortex. Since hormone imbalances are known to be associated with affective illness, the present study was undertaken to determine whether sex hormones influence these alterations in neurotransmitter receptor binding. Using receptor binding assays, we found that castration abolishes the decline in the concentration of 5-HT2, but not beta-adrenergic, receptors brought on by chronic imipramine or iprindole treatment in both male and female rats. In contrast, the receptor responses to trazodone, mianserin, and pargyline were not influenced by surgery. Furthermore, mianserin was found to reduce beta-adrenergic binding in intact females, but not males, suggesting a sex-related specificity with regard to the response to this agent. Testosterone and estrogen, but not dihydrotestosterone, reversed the effects of castration in males, suggesting that the interaction between the steroids and antidepressants is mediated through estrogenic, rather than androgenic, receptors. The results indicate that the receptor responses to some antidepressant drugs is dependent, at least in part, on the hormonal state of the animals.