The is an application for an ADAMHA Research Scientist Award (Level II). The candidate will use the award to devote his full professional energies to research projects at the interface of psychiatry, sleep disorders medicine and circadian rhythms. He will focus particularly on the development of melatonin as a treatment for disorders of circadian phase. 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 this project, the constraining effects of the light-dark cycle will be evaluated by giving melatonin to both blind and sighted subjects. The parameters that produce the maximal phase-advancing effects in both groups will be defined by varying the timing, dose and duration of melatonin administration. An attempt to enhance the phase-advancing effects of exogenous melatonin will be made by the co-administration of melatonin with atenolol, a drug that suppresses endogenous melatonin production by blocking pineal beta adrenergic receptors. After defining the optimal treatment parameters, 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) will be tested. The phase-advancing effects of exogenous melatonin administration will be evaluated 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. These studies may lead to the use of melatonin as a way to treat both blind and sighted patients with abnormal circadian rhythms.
