Pharmacologic restoration of suppressed temperature rhythms in rats by melatonin, melatonin receptor agonist, S20242, or 8-OH-DPAT

Abstract Endogenous circadian rhythms in body temperature and locomotor activity rhythms are suppressed in Sprague–Dawley rats exposed to prolonged continuous light, possibly as a result of a profound alteration of the melatonin secretion rhythm. The ability to restore circadian system function with either exogenous melatonin, or melatonin receptor agonist S20242 ( N -[2-(7-methoxy napth-1-yl)ethyl] propionamide), or 5-HT 1A receptor agonist, 8-hydroxy-2-(di- n -propylamino)tetralin (8-OH-DPAT), was investigated under these conditions. Seven rats received a daily 6-h intravenous infusion of melatonin (0.01 mg kg −1 ) for 10 days, which generates a nearly physiological circadian rhythm of urinary 6-sulfatoxy-melatonin, the main urinary metabolite of melatonin. Nevertheless, there was no effect on body temperature or locomotor activity rhythms. Then, 49 rats received daily subcutaneous melatonin (0.01, 1 or 5 mg kg −1 day −1 ), S20242 (1 or 5 mg kg −1 day −1 ) or 8-OH-DPAT (5 mg kg −1 day −1 ) for 30 days. The circadian rhythm in body temperature was restored by subcutaneous melatonin or by S20242 as a function of the dose or by 8-OH-DPAT. The effect started within the first 10 days of treatment and persisted for 1 to 3 weeks following the end of treatment in 8 of 10 rats receiving melatonin, in 9 of 11 rats treated with S20242 and in 1 of 4 rats treated with 8-OH-DPAT. Activity was less susceptible to entrainment than temperature with these drugs, since circadian rhythmicity was restored in only 2 of 6 rats treated with melatonin and in 1 of 4 rats treated with 8-OH-DPAT. These data demonstrate a specific action of subcutaneous melatonin, S20242 or 8-OH-DPAT on temperature rather than on activity rhythms. This differential effect on two major outputs of the suprachiasmatic nucleus further supports the existence of two independent oscillators in this hypothalamic circadian clock, which may be considered as separate pharmacological targets in the circadian system.