Ž . Brain Research 762 1997 185–194 Research report Comparative effects of a melatonin agonist on the circadian system in mice and Syrian hamsters O. Van Reeth a,b, ) , E. Olivares a , Y. Zhang b , P.C. Zee b , E. Mocaer c , R. Defrance c , F.W. Turek a,b a Centre des Rythmes Biologiques, School of Medicine, Hopital Erasme, UniÕersite Libre de Bruxelles, Route de Lennik, 808, 1070 Brussels, Belgium ˆ ´ b Center for Circadian Biology and Medicine, Departments of Neurobiology r Physiology and Neurology, Northwestern UniÕersity, EÕanston and Chicago, IL, USA c Departement de Neurobiologie, Institut de Recherches Internationales SERVIER, CourbeÕoie, France ´ Accepted 18 March 1997 Abstract S-20098 has potent and specific agonist properties on melatonin receptors both in vitro and in vivo. Behavioral studies on rodents already showed that repeated intraperitoneal administration of S-20098 could dose-dependently alter the functioning of the circadian clock. To determine whether single administration of S-20098 could alter the circadian rhythms of rodents, we first used the Ž . Ž . phase-response curve PRC approach in two different species: Syrian hamsters and mice C3HrHeJ . Our results show that the shape, circadian times and extent of the PRC to S-20098 look very similar in mice and hamsters. In both species, the phase advance portion of the PRC to S-20098 is limited to a 3 h window preceding the onset of locomotor activity, but the magnitude of phase shifts is larger in mice. We also tested the phase shifting effects of increasing doses of S-20098 during the interval of maximal sensitivity to this compound. Treatment with S-20098 induces dose-dependent phase shifts, with maximal shifts observed after injections of 20 and 25 mgrkg S-20098 i.p., respectively, in mice and hamsters. Those results are in agreement with the limited distribution of melatonin-binding sites within the circadian clock of adult Syrian hamsters, as compared to other rodents. q 1997 Elsevier Science B.V. Keywords: Circadian; Rhythm; Clock; Melatonin; Agonist; Mice; Syrian hamster 1. Introduction In mammals, the pineal hormone melatonin is impli- cated in a large number of physiological processes, includ- wx ing circadian clock regulation 3 . In various mammalian species, including humans, melatonin receptors are present Ž . in the hypothalamic suprachiasmatic nucleus SCN , the w x location of the central circadian clock 22,39 . Administra- tion of exogenous melatonin at selected circadian times has been shown to affect phase andror period of the circadian clock. In rats and hamsters, acute melatonin treatment can induce phase shifts in the circadian rhythm w x of locomotor activity 4,17,38 . In mice free-running in constant darkness, administration of melatonin for 3 con- ) Ž. Corresponding author at address ‘a’. Fax: q32 2 555-3569; E-mail: ovanree@resulb.ulb.ac.be secutive days at the same clock time induces phase shifts wx in the activity rhythm 5 . Appropriately timed administra- tion of melatonin can accelerate the rate of re-entrainment of circadian rhythms in rats subjected to an abrupt shift in w x the light-dark cycle 29 . Repeated daily injections of melatonin can entrain the circadian activity rhythm in rats w x free-running in constant environmental conditions 27 . In humans, administration of melatonin can phase shift circa- w x dian rhythms 20,31 and improve mood andror sleep w x w x disruption in jet lag 26 or shift work 13 . Pharmacologi- cal doses of melatonin can also promote andror improve w x w x sleep in young adults 42 and in insomniac patients 14,25 . In vitro and in vivo animal studies indicate that S-20098 has potent and specific agonist properties on melatonin w x receptors 7,41 . In vitro comparison of the effects of S-20098 and melatonin on the firing rate of SCN neurons reveals a similar dependence on circadian phase- and w x dose-response relations for the two compounds 11 . 0006-8993r97r$17.00 q 1997 Elsevier Science B.V. All rights reserved. Ž . PII S0006-8993 97 00382-X