PRIMATE MODEL FOR THE HYPNOTIC EFFECTS OF MELATONIN

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Aging is associated with sleep disturbances, and with disruptions in circadian rhythms, including that in serum melatonin concentrations: nocturnal serum melatonin levels in the elderly are often substantially lower than in younger people. Physiologic and pharmacologic doses of melatonin, that raise circulating melatonin concentrations to level normally occurring nocturnally or well above it, were shown to produce acute daytime fatigue and sleepiness, to diminish performance, and to significantly reduce latency to sleep onset both in young healthy subjects and in elderly insomniacs. The mechanisms underlying these effects are not known. In order to understand the mechanisms by which melatonin acts on human sleep and behavior, it would be helpful to have an animal model in which, as in humans, the physiological nocturnal increase in melatonin secretion correlates with nocturnal sleep, i.e., in a diurnal animal species. We propose to conduct a pilot study using Macaca Nemestrina, designed to explore, in this non-human primate, the hypotheses that: 1. Oral melatonin treatment decreases motor activity, promotes earlier sleep onset, and increases sleep efficiency, as assessed actigraphically. 2. The magnitude and the duration of behavioral and sleep-promoting effects of melatonin is dose dependent, and; 3. This primate model will allow detection of possible changes in melatonin's effect on sleep and behavior during a prolonged, 2 month, treatment period using a minimum effective dose of the hormone. If such an animal model can be developed it will allow us to further explore: 1. The neurophysiologic and biochemical mechanisms that underlie melatonin's sleep-promoting and behavioral effects; 2. The physiologic basis of the interindividual variability in melatonin's effects, that has been observed in humans, and; 3. The possible causal relationship between the age-related deterioration in sleep patterns and a decrease in pineal secretory activity. This knowledge may ultimately lead to the development of an experimentally-based strategy for melatonin-replacement therapy in elderly humans.