Involvement of the hypothalamus–pituitary–adrenal axis in antidepressant activity of corticotropin-releasing factor subtype 1 receptor antagonists in the rat learned helplessness test

Effects of corticotropin-releasing factor (CRF) subtype 1 receptor antagonists on learned helplessness (LH) were examined in rats. Repeated administration of CRF 1 receptor antagonists, CRA1000 (3 mg/kg, po) and CP-154,526 (10 mg/kg, po), and tricyclic antidepressant, imipramine (10 mg/kg, po), for 8 days significantly decreased the number of escape failures in LH. On the other hand, acute treatment of adrenocorticotropin (ACTH) abolished the decreased number of escape failures seen with imipramine. Likewise, in this ACTH model, the CRA1000- and CP-154,526-induced decrease in the number of escape failures was no longer observed. The CRF 1 receptor is apparently involved in the produced escape failures in LH, and the attenuated LH seen with CRF 1 receptor antagonists was abolished by ACTH. It would thus appear that the attenuated LH seen with CRF 1 receptor antagonists depends on the hypothalamus–pituitary–adrenal (HPA) axis.