Entrainment of rat circadian rhythms by melatonin does not depend on the serotonergic afferents to the suprachiasmatic nuclei.

Daily administration of melatonin (MEL) can entrain rat circadian rhythms free-running in constant darkness. The high MEL doses needed to obtain entrainment suggest the implication of other neural mechanisms than simply an effect on the hormone's specific receptors detected in the SCN. Administration of serotonin receptor agonists can phase-shift the rodent circadian clock, and MEL is known to modulate release and reuptake of serotonin in nerve endings. This raises the question of a critical involvement of 5-HT-fibres in the entraining properties of MEL. The aim of the present study was to test this hypothesis. Bilateral neurotoxic (5,7-dihydroxytryptamine) lesions of the serotonergic fibres in the SCN were performed in animals kept in LD 12:12. Following the post-operative period, the animals were transferred to constant darkness to free-run. MEL was then administered by a 1 h daily infusion. Both well lesioned and intact animals entrained to MEL. No differences were observed between lesioned and control animals on parameters such as the phase-angles between MEL onset and activity onset, and core body temperature acrophase, respectively. Entrainment of rat circadian rhythms to exogenous MEL is thus not directly dependent on the 5-HT fibres in the SCN.

Influence of the mode of daily melatonin administration on entrainment of rat circadian rhythms.

In previous entrainment studies, melatonin (MEL) was administered by handling the animal, but because such handling may act as a confounding variable, the results from these studies are equivocal. The authors used MEL administration techniques that do not involve direct handling of the animal. Long Evans rats were used, and core body temperature (CBT) and wheel-running activity were recorded. One group of rats received a daily 1-h time-fixed infusion of MEL or the vehicle via a subcutaneous catheter. Animals in a second group had timed access to drinking water involving daily presence of drinking water containing MEL or the vehicle for 2 h at a fixed time of the day. Following entrainment to LD 12:12, both groups were transferred to constant darkness to free-run under vehicle administration. MEL was then administered, and entrainment occurred when activity onset coincided with MEL onset. Under both regimens, entrainment of wheel-running and CBT rhythms showed equal phase-relation to the onset of MEL administration, and free-running reoccurred when MEL was withdrawn. The authors concluded that MEL administration via drinking water and via infusion represent efficient ways to synchronize free-running rhythms in rats.

Does melatonin have an effect on cognitive performance?

Exogeneous melatonin causes phase shifts of circadian rhythms, reduces core body temperature, and induces drowsiness, but dispute still surrounds the hormone's effect on cognitive performance. Using a N = 1 double-blind alternating treatments design, daytime performance on four cognitive tests (logical reasoning, serial add/subtract, visual-spatial, and four-choice reaction time tasks) was measured after PO doses of placebo and 1.6 mg melatonin. Serum melatonin and core body temperature were also recorded. Performance was measured during time windows corresponding to the serum melatonin peak and the temperature trough respectively, following melatonin administration. The data showed that performance speed and accuracy measures were not affected during the serum melatonin peak, but that reaction times on all cognitive tasks increased substantially during the temperature trough. These results suggest that circulating melatonin has no direct and immediate effect on cortical information processing, and that the reduction in cognitive processing speed during body temperature trough occurs as a consequence of the hormone's hypothermic properties, causing a slowing down of cerebral processing speed.