The effects of acute chronic administration of tricyclic antidepressants on the pituitary-adrenal axis were studied in adult male rats. Acute administration of desipramine, imipramine and chlorimipramine activated the pituitary-adrenal axis. The effect of imipramine was found to be of short duration with a significant increase at 30 and 60 min after the administration of the drug and a return to baseline levels at 180 min. The effect of imipramine was dose-dependent. Twenty hours after the last drug administration rats chronically injected with chlorimipramine showed normal basal and saline-induced levels of corticosterone. However the response of these rats to an acute dose of chlorimipramine was significantly lower than that of drug-naive rats, indicating tolerance to the drug. The mechanisms involved in the activation of the pituitary-adrenal axis caused by antidepressants and the tolerance to repeated drug administration are still unknown.