Experimental evidence suggests that while the administration of choline may not alter the steady-state concentration or turnover of acetylcholine (ACh) in brain under """"""""normal"""""""" physiological conditions, it does enhance the synthesis of ACh under conditions of increased neuronal demand for or a decreased endogenous supply of the neurotransmitter precursor. Although the specific mechanisms involved in the utilization of exogenous choline for the synthesis of ACh during conditions of increased neuronal activity have not yet been elucidated, results indicate that the mobilization of free choline from specific pools of bound choline plays a significant role. Furthermore, evidence suggests that the mechanisms regulating the metabolism of ACh may depend on the functional state of cholinergic neuronal activity. Hence, it is the specific aim of this research proposal to investigate further the relationships among neuronal activity, the disposition and utilization of administered choline and central cholinergic mechanisms. These studies will involve measurements of: synaptosomal choline uptake; steady-state concentrations of ACh, choline, phosphorylcholine, CDP-choline, glycerophosphorylcholine, lysophosphatidylcholine and phosphatidylcholine; and the incorporation of choline into and release from choline-containing compounds. Choline will be administered through injection and by dietary supplementation and cholinergic neuronal activity in various brain regions will be altered by pharmacological and physical manipulations. Results from these studies will provide valuable information on the relationship between neurotransmitter precursor availability and the activity of central cholinergic neurons which is essential for understanding the intrinsic mechanisms involved in the regulation of the metabolism of choline and ACh in brain. Furthermore, results will provide a basis to better assess the therapeutic rationale for and possible merits of the use of choline for the treatment of neuropsychiatric disorders postulated to involve hypocholinergic activity such as tardive dyskinesia, mania, Huntington's disease and Alzheimer senile dementia.
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