Naltrexone-insensitive facilitation and naltrexone-sensitive inhibition of passive avoidance behavior of the ACTH-(4-9) analog (ORG 2766) are located in two different parts of the molecule.

Subcutaneous injection of the ACTH-(4-9) analog (OG 2766) in ng amounts prior to the retention test facilitated, while microgram doses attenuated passive avoidance behavior. The inhibitory effect could easily be overcome by treatment with ACTH-(1-10) either before or after ORG 2766 administration. Thus, inhibition of passive avoidance behavior by ORG 2766 probably was not due to competition with ACTH-like peptides or a functional antagonistic influence on brain structures sensitive to ACTH-like peptides. Intracerebroventricular administration of ACTH-(4-10) in a wide dose range (0.5-10.0 micrograms) and of ORG 2766 in low doses (0.5-1.0 ng) facilitated passive avoidance behavior, whereas 'high' doses of ORG 2766 (5.0 and 10.0 ng) and graded doses of COOH terminal tripeptide of ORG 2766 (Phe-D-Lys-Phe; PDLP; 0.5-10.0 ng) attenuated passive avoidance behavior. The NH2 terminal tetrapeptide of ORG 2766 (H-Met/O2/-Glu-His-Phe) facilitated passive avoidance behavior, whereas the NH2 terminal tripeptide (H-Met/O2/-Glu-His) was ineffective. Naltrexone pretreatment antagonized the attenuating effect of ORG 2766 and PDLP. Following pretreatment with this opiate antagonist both 'low' and 'high' doses of ORG 2766 and the NH2 terminal tetrapeptide of ORG 2766 induced facilitation of passive avoidance behavior, while PDLP was ineffective in the presence of naltrexone. Thus, ORG 2766 exerts a dual effect on passive avoidance behavior. The facilitating effect of ORG 2766 resides in the NH2 terminal part and is unrelated to naltrexone-sensitive brain opiate receptor sites, whereas the inhibiting influence is located in the COOH terminal part of the peptide and depends on naltrexone-sensitive brain opiate receptor sites.