Our long term goal is to understand the functional, biochemical and molecular properties of melatonin receptors. The overall goal of this application is to determine whether the activation of melatonin receptors along the circadian timing system modify photic entrainment in the C3H/HeN mouse. Melatonin, produced in the pineal gland of the C3H/HeN mouse, regulates circadian activity rhythms through activation of melatonin receptors in the suprachiasmatic nuclei when administered alone. We hypothesize that the circadian production of endogenous melatonin modulates the phase shifting effect of light within the suprachiasmatic nuclei and possibly within the retina. We propose to determine circadian rhythms of melatonin production and melatonin receptor sensitivity and to assess the effect(s) of melatonin on phase shifts of circadian activity rhythms and on an efferent target of the suprachiasmatic nuclei, the paraventricular nuclei. To investigate the involvement of melatonin in the circadian sensitivity to light in the retina and suprachiasmatic nuclei of C3H/HeN mice we will determine: l) The circadian rhythms of melatonin production in the pineal, retina, and serum, and of melatonin receptor sensitivity and mRNA expression in the retina and suprachiasmatic nuclei; 2) The effect of endogenous melatonin production on melatonin receptor sensitivity and mRNA expression by comparing receptor rhythms in intact C3H/HeN mice with rhythms in mice depleted of endogenous melatonin by pinealectomy or pretreatment with nadalol (beta blocker); 3) The effect of endogenous melatonin on the light-induced phase shifts of circadian activity rhythms in pinealectomized or nadalol treated mice, or in mice treated with the melatonin receptor antagonists luzindole or 4-P-PDOT; 4) The effect of exogenous administration of melatonin on light-induced phase shifts of circadian activity rhythms; 5) The effect of melatonin receptor activation by endogenous and exogenous melatonin in the suprachiasmatic nuclei on the neuronal activity in one of its efferent targets, the paraventricular nucleus of the hypothalamus. The proposed studies will provide information on melatonin receptor sensitivity in the retina and the pacemaker, and on the role of melatonin receptor activation on the light-induced phase shifts of circadian activity rhythms. They may help to unravel the role of melatonin and light on the etiology of disorders associated with changes in photoperiod and season (e.g., jet lag, advanced and delayed sleep phase syndrome, seasonal affective disorders).
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