We examined the effects of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test with the administration of imipramine, desipramine, or lithium. A single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) significantly decreased the duration of immobility in normal rats in a dose-dependent manner. Lithium (10-100 mg/kg, p.o.), however, had no affect on the performance of rats in the forced swim test. ACTH (100 microg/day), administered subcutaneously to rats for 1, 3, 7, and 14 days, had no apparent effect on the duration of immobility in this test. The immobility-decreasing effect induced by a single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) was blocked by chronic administration of ACTH for 3-14 days. The reduction of immobility, induced by chronic administration of imipramine (10 mg/kg, i.p.) for 15 days, was blocked by treatment with ACTH for 14 days. When lithium (100 mg/kg, p.o.) was administered for 15 days concurrently with imipramine (10 mg/kg, i.p.), we observed a significant decrease in immobility in rats treated with ACTH for 14 days. We suggest that chronic treatment of rats with ACTH may prove to be an effective model of tricyclic antidepressants-treatment-resistant depression.