Chronic (21 days) antidepressant administration to rats results in a decrease in both serotonin and β-adrenergic but not cholinergic muscarinic, receptor binding in selected brain regions, with the frontal cortex appearing to be somewhat more sensitive to this effect. Neither nisoxetine nor fluoxetine, potent and specific inhibitors of norepinephrine and serotonin uptake respectively, caused receptor binding changes after chronic administration, suggesting that inhibition of transmitter uptake, in itself, in insufficient to cause receptor subsensitivity. In vitro experiments indicated that antidepressants are relatively weak α₂-receptor blocking agents, but some are potent on the α₁-receptor system indicating that the norepinephrine releasing potency of some antidepressants may not be mediated by blockade of presynaptic autoreceptors.