Hypophysectomy resulted in a marked impaired acquisition of shuttle-box avoidance learning, when lower shock intensity (0.05 mA) was used as the unconditioned stimulus, but not when shock intensity was increased to 0.12 mA. Daily subcutaneous treatment with ACTH4-10 (6 micrograms/day), ACTH4-7 (6 micrograms/day), [Met(O2)4]ACTH4-7 (2 micrograms/day), ACTH4-9 analog (Org 2766) (60 ng/day), and an ACTH4-16 analog (HP 953 A) (60 ng/day) for 7 days normalized avoidance acquisition of hypophysectomized rats during the treatment period. The beneficial effect of the peptides was of a short-term nature, since it disappeared after discontinuation of the treatment. Microgram amounts of Org 2766 did not influence acquisition of hypophysectomized rats. [D-Phe7]ACTH4-10 (60 micrograms/day) further reduced the already deficient acquisition of avoidance behavior of hypophysectomized rats. This latter effect may be due to an antagonistic effect towards brain-borne ACTH-related peptides. ACTH1-16 -NH2 antiserum administered intracerebroventricularly 30 min prior to a massed-trial shuttle-box acquisition session reduced avoidance acquisition in hypophysectomized rats. This suggests that in addition to ACTH and related peptides from the pituitary, brain-borne ACTH-like peptides are involved in avoidance learning.