Behavioural Brain Research 106 (1999) 181 – 188 Research report Early postnatal treatment with ACTH 4-9 analog ORG 2766 improves adult spatial learning but does not affect behavioural stress reactivity K.M. Horva ´th a, *, P. Meerlo a , K. Felszeghy b , C. Nyakas a,b , P.G.M. Luiten a a Department of Animal Physiology, Graduate School of Behaioural and Cognitie Neurosciences, Uniersity of Groningen, P.O. Box 14, 9750 AA Haren, The Netherlands b Central Research Diision, Haynal Uniersity of Health Sciences, Budapest, Hungary Received 26 April 1999; received in revised form 8 July 1999; accepted 8 July 1999 Abstract Studies on adult animals and humans have shown that the ACTH 4-9 analog ORG 2766 influences cognitive performance and possibly has neurotrophic effects. For this reason we studied the effect of ORG 2766 applied in early postnatal life when brain structures and neuronal pathways are still developing. Our aim was to see whether such treatment during development would result in permanent changes in adult behavioural performance. Pups received subcutaneous injections of 1 g/g bodyweight ACTH 4-9 analog ORG 2766 on day 1, 3 and 5 after birth. Control animals in the same nest received saline injections. When the animals had reached an adult age of 3 months they were subjected to a series of tests to measure their behavioural performance. In the first experiment, behavioural stress responses and anxiety were measured by subjecting the rats to the following tests: open field, defensive burying, elevated plus maze, and conditioned fear test. In a second experiment, adult cognitive function was measured in the Morris water-maze, a hippocampus-related spatial learning test, and in the active avoidance test, a more amygdala-related nonspatial test. The results showed that animals treated with ORG 2766 during early postnatal life learned faster in the spatial Morris water-maze. The treatment had a positive effect on performance during the acquisition phase of the learning task, while memory retrieval was not affected. Learning in the nonspatial active avoidance task did not change due to the postnatal ACTH 4-9 treatment. In addition, there were no differences in the open field test, the defensive burying test, elevated plus maze and the conditioned fear test. The latter supports the conclusion that the differences in water-maze performance was due to a difference in learning speed, rather than a difference in anxiety or behavioural stress reactivity. Analysis of [ 3 H]CORT binding capacity measured after the learning tests revealed no differences in the hippocampal MR and GR concentration between non-treated and treated animals. © 1999 Elsevier Science B.V. All rights reserved. Keywords: Postnatal; ACTH 4-9 ; Learning; Memory; Morris water-maze; MR; Anxiety; Stress www.elsevier.com/locate/bbr 1. Introduction In the last three decades, an increasing number of studies have shown that neuropeptides play a promi- nent role in the neuronal regulation of behavioural processes, particularly of learning and memory. This area of study originated from the observation that impaired acquisition in avoidance tasks after removal of the pituitary gland can be restored by administration of the native adrenocorticotropic hormone ACTH [6]. Ever since, studies have been undertaken with special emphasis on neuropeptides derived from the amino-ter- minal half of ACTH. Such ACTH fragments are able to produce the cognitive effect of ACTH while their * Corresponding author. Tel.: +31-50-3632363; fax: +31-50- 3635205. E-mail address: k.m.horvath@biol.rug.nl (K.M. Horva ´th) 0166-4328/99/$ - see front matter © 1999 Elsevier Science B.V. All rights reserved. PII:S0166-4328(99)00106-0