EFFECT OF MELATONIN ON HUMAN CIRCADIAN RHYTHMS

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Melatonin is a hormone produced by the pineal gland at night that may be involved in the natural regulation of circadian rhythms. Animal studies have shown that exogenous melatonin administration can synchronize "free- running" circadian rhythms and can accelerate the rate of adaptation to a new rest/activity cycle. In studies currently in progress, we administered melatonin orally to five totally blind subjects with free-running endogenous melatonin rhythms in an attempt to entrain them to a 24-hour day. Although entrainment did not result, melatonin treatment produced large phase advances in the endogenous melatonin rhythms. These advances are much more robust than when melatonin is given to sighted people, possibly because the competing time cues from the light-dark cycle are not present in the blind subjects. In this project, we will evaluate the constraining effects of the light- dark cycle by giving melatonin to both blind and sighted subjects. We will define the parameters that produce the maximal phase-advancing effects in both groups by varying the timing, dose and duration of melatonin administration. We will attempt to enhance the phase-advancing effects of exogenous melatonin administration by suppressing endogenous melatonin production with the drug atenolol will test the effects of melatonin in sighted subjects who are adapting to an abrupt advance of their sleep-wake cycle (a laboratory model of shift work adaptation). We will evaluate the phase-advancing effects of exogenous melatonin administration by measuring its effect on the timing (phase) of endogenous melatonin production by the pineal gland. Phase will be assessed by obtaining serial blood samples and measuring plasma melatonin concentrations to determine the precise "onset" of active production. An RIA will be employed for efficiently processing most of the samples but critical values around the time of the melatonin onset will be verified with a highly specific gas chromatographic negative ion mass spectrometric assay. These studies may lead to the use of melatonin as a way to treat both blind and sighted patients with abnormal circadian rhythms.