SLEEP/WAKE RHYTHMS IN AGING--TREATMENT WITH NIMODIPINE

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The purpose of this project is to gain a basic understanding of the causes of chronic sleep disturbances in older adults and to develop effective therapies for these problems. Altering the age-related changes in the endogenous circadian pacemaker and reducing exposure to bright light can improve the sleep performance in elderly persons. However, age-related changes in synaptic plasticity arising from impaired calcium regulation may decrease the responsiveness of the aging clock to light. Recent findings indicate that treatment with the L-type calcium channel antagonist, nimodipine, can improve light-induced phase shifts of circadian activity rhythms in old mice. This indicates that nimodipine may also improve the response of the clock to light. The goals of this project are to test the hypothesis that responsiveness to light is decreased in the clock of older humans, and that enhancing the responsiveness of the clock to light with nimodipine will normalize disrupted sleep/wake rhythms in an animal model of aging. The specific aims of the project are to 1) assess the conditions under which nimodipine reverse age-related deficits in responsiveness of the clock to light in mice by testing the effects of different treatment regimens on three measures of circadian responsiveness to light in young, middle aged, and old mice; 2) test the hypothesis that nimodipine will restore normal entrainment patterns to a light/dark cycle in aged C3H/HeN mice by measuring the amplitude of the diurnal activity rhythm and the phase angle of entrainment; 3) test the hypothesis that older humans exhibit a decrease in the responsiveness of the clock to light by assessing the light-induced suppression of nocturnal melatonin levels and phase shifts of circadian rhythms in young and old subjects; and 4) determine the light intensity required to improve sleep and daytime performance in elderly subjects by assessing the effect of daily administration of three different intensities of light on neuropsychological performance and sleep in older adults. The results of the animal and human experiments are designed to determine if nimodipine can enhance the effectiveness of light therapy for sleep/wake disorders in elderly humans.