ENTRAINMENT OF RAT CIRCADIAN-RHYTHMS BY THE MELATONIN AGONIST S-20098REQUIRES INTACT SUPRACHIASMATIC NUCLEI BUT NOT THE PINEAL

S-20098 is a potent nonindolic melatonin agonist that has been shown t o entrain free-running circadian rhythms. The current experiments exam ined the role of the suprachiasmatic nuclei (SCN) and of the pineal gl and in the entrainment of circadian rhythms by S-20098. First, daily i njections of S-20098 (1 and 10 mg/kg s.c.) were administered to SCN-an d sham-lesioned rats. At both dose levels, circadian effects were note d in all sham-lesioned animals. Locomotor activity and body temperatur e rhythms in 3 of 5 sham-lesioned rats were entrained by the daily inj ections. In SCN-lesioned rats, S-20098 had no synchronizing or entrain ing effects at either dose level. These results show that S-20098 exer ts its entraining effects on circadian rhythms via the circadian pacem aker located in the SCN. Second, the effects of daily injections of S- 20098 (10 mg/kg s.c.) were examined in pinealectomized, sham-pinealect omized and intact rats. All rats receiving S-20098, irrespective of su rgical treatment, showed circadian changes. Rhythms in 81% of these an imals entrained to daily administration of the compound, indicating th at entrainment induced by S-20098 does not depend on an intact pineal. When injected with 10 mg/kg S-20098, 69% of rats, irrespective of sur gical treatment, showed long-term modifications of free-running period that still were evident several weeks after administration ceased. If confirmed, this finding may have therapeutic implications in humans r egarding the optimal mode and administration of S-20098 in a clinical setting.