The goal of the core project of this Physician Scientist Award application is to investigate specific neurotransmitter receptors in the circadian timekeeping system. There is substantial evidence that one oscillator which drives circadian rhythms, perhaps the master oscillator, is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. However, despite this anatomic evidence, the neurochemical basis of the generation and modulation of circadian rhythms is poorly understood. Several studies have implicated the nicotinic cholinergic, gamma- aminobutyric acid (GABA) ergic, serotonergic, and beta adrenergic neurotransmitter systems in the control of circadian rhythmicity. The work of this project will investigate the neurotransmitter receptors of these four systems using quantitative autoradiography, a technique which allows the simultaneous assessment of multiple contiguous brain areas which may be functionally interrelated, as in the circadian timekeeping system. These receptors will be studied in (1) the SCN; (2) an efferent projection area of the SCN, the paraventricular nuclei of the hypothalamus; and (3) an area of the brain not directly involved in circadian timekeeping, the frontoparietal cortex. We will investigate whether these receptors themselves manifest the properties expected of other circadian rhythms. This issue will be studied by assessing the effect of two well defined zeitgebers (time-cues), light and the pineal hormone melatonin, on these receptors. Two circadian rhythms controlled by the SCN will be monitored in the same animals in which the receptors are assessed. Further understanding of the neuropharmacologic basis of circadian rhythmicity will ultimately allow for the design of more effective treatments for depression and manic-depressive illness, in which such rhythms appear to be disrupted and may plan a pathogenic role.
