Experimental evidence to date indicate that although supplementation with choline does not alter the steady-state concentration of acetylcholine (ACh) in brain under normal biochemical and physiological conditions, it does support the synthesis of ACh during drug-induced increases in neuronal demand. Although the specific mechanisms involved in the utilization of supplemental choline for the synthesis of ACh during states of increased neuronal activity have not yet been elucidated, results indicate that this effect is not due to increased levels of free choline in brain, but rather, may involve alterations in the concentration or metabolism of choline-containing compounds. Hence, it is the overall objective of this research proposal to investigate the neurochemical mechanisms mediating the effects of choline supplementation. Neurochemical and neuropharmacological techniques will be used to address the following questions: 1) Do chronic alterations in the availability of choline alter the dynamics of ACh metabolism? 2) Is the utilization of supplemental choline for the synthesis of ACh dependent on the level of activity of cholinergic neurons? 3) What are the sources of choline mediating the effects of choline supplementation? 4) What are the mechanisms regulating the metabolism of choline at nerve terminals? 5) What is the nature and physiological significance of the serum factor whose activity or concentration is induced by choline supplementation and whose role may be to regulate the transport of choline across the blood-brain barrier? 6) What are the functional consequences of choline supplementation? and 7) Are the effects of choline supplementation observed in brain from adult rats manifest in brain from aged animals? Results from these studies will provide information on the relationship between neurotransmitter precursor availability and central cholinergic mechanisms which is essential for understanding the intrinsic mechanisms regulating the metabolism of choline and ACh in brain. Furthermore, results may provide a basis to better assess the therapeutic rationale and possible merits of the use of choline for the treatment of neuropsychiatric disorders postulated to involve hypocholinergic activity such as Alzheimer's Disease.
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