ELSEVIER PII S0031-9384(96)00034-1 Physiology & Behavior, Vol. 60, No. 2, 397-401, 1996 Copyright © 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0031-9384/96 $15.00 + .00 IRI-514, a Synthetic Peptide Analogue of Thymopentin, Reduces the Behavioral Response to Social Stress in Rats FREDERIQUE MENZAGHI, .1 STEPHEN C. HEINRICHS, .2 MAURICIO VARGAS-CORTES,t GIDEON GOLDSTEINt AND GEORGE F. KOOB* *The Scripps Research Institute, Department of Neuropharmacology, CVN 7, 10666 North Torrey Pines Road, La Jolla, CA 92037 USA and tlmmunobiology Research Institute, Route 22 East, P.O. Box 999, Annandale, NJ 08801-0999 USA Received 13 July 1995 MENZAGHI, F., S. C. HEINRICHS, M. VARGAS-CORTES, G. GOLDSTEIN AND G. F. KOOB. IRI-514, a synthetic peptide analogue of thymopentin, reduces the behavioral response to social stress in rats. PHYSIOL BEHAV 60(2) 397-401, 1996.--Thymopentin, a synthetic pentapeptide (Arg-Lys-Asp-Val-Tyr) corresponding to amino acids 32-36 of the thymic polypeptide thymopoietin, has been reported to block adrenocorticotrope responses to stress. The purpose of the present study was to explore potential antistress properties of a synthetic analogue of thymopentin, IRI-514 (Ac-Arg-Pro-Asp-Phe-NH 2) using a behavioral response to a stressor. The behavioral response to social conflict stress (resident-intruder paradigm) was evaluated by the elevated plus-maze test of anxiety in adult Wistar rats. A single subcutaneous (SC) administration of IRI-514, 48 h before stress, dose-dependently reversed the anxiety-like behavior induced by the social stress. The effect of IRI-514 was present over an extended period (24-72 h) following SC administration and was maximally effective at a dose of 1 mg/kg. These results indicate that IRI-514 has a long-lasting modulatory effect on behavioral responses to a stressor, and suggest that thymopoietin-derived peptides may have a role in modulating both behavioral and neuroendocrine responses to stress. Resident-intruder paradigm Social stress Thymopentin Corticotropin-releasing factor Elevated plus-maze Nicotinic receptors Thymic peptide Anxiety THE thymopoietin (TP) gene encodes three nuclear proteins, TPct, TP[3, and TP~/, by alternative mRNA splicing (14). These proteins share their N-terminal 187 amino acids, and a protein corresponding to the N-terminal 49 amino acids was originally isolated from calf thymus utilizing a delayed effect in vivo on neuromuscular transmission (8,29). Subsequently, TP was found to have immunoregulatory properties, including the induction of early T-cell differentiation (1,20,28) and the modulation of the activity of mature lymphocytes (21,31). The biologic activity of thymopoietin resides in a pentapeptide corresponding to amino acids 32-36 (thymopentin) (Arg-Lys-Asp-Val-Tyr), which re- tains a variety of immunoregulatory influences (9). Subsequent reports indicated that thymopentin also exerted specific neuro- modulatory effects. Intraperitoneal injection of thymopentin blocked the anxiogenic-like effects of a [3-carboline drug in an elevated plus-maze test of anxiety in rats (19). In addition, thymopentin prevented stress-induced corticosterone elevation, suggesting that thymopentin may have stress-protective effects in rodents (19). The purpose of the present study was to explore the potential antistress properties of a synthetic analogue of thymopentin, IRI-514 (Ac-Arg-Pro-Asp-Phe-NH2), using a behavioral re- 1 Requests for reprints should be addressed to Frederique Menzaghi, SIBIA Neurosciences, Inc., 505 Coast Boulevard South, Suite 300, La Jolla, CA 92037-4641. 2 Present address: Neurocrine Biosciences, Inc., 3050 Science Park Rd., La Jolla, CA 92037. 397