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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH033443-06
Application #
3375405
Study Section
(BPNA)
Project Start
1979-12-01
Project End
1986-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
6
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Louisiana State University Hsc New Orleans
Department
Type
School of Medicine & Dentistry
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Anandatheerthavarada, H K; Williams, J F; Wecker, L (1993) Differential effect of chronic nicotine administration on brain cytochrome P4501A1/2 and P4502E1. Biochem Biophys Res Commun 194:312-8
Coutcher, J B; Cawley, G; Wecker, L (1992) Dietary choline supplementation increases the density of nicotine binding sites in rat brain. J Pharmacol Exp Ther 262:1128-32
Zawia, N; Arendash, G W; Wecker, L (1992) Basal forebrain cholinergic neurons in aged rat brain are more susceptible to ibotenate-induced degeneration than neurons in young adult brain. Brain Res 589:333-7
Welsh, B; Wecker, L (1991) Effects of streptozotocin-induced diabetes on acetylcholine metabolism in rat brain. Neurochem Res 16:453-60
Wecker, L (1991) The synthesis and release of acetylcholine by depolarized hippocampal slices is increased by increased choline available in vitro prior to stimulation. J Neurochem 57:1119-27
Wecker, L (1990) Dietary choline: a limiting factor for the synthesis of acetylcholine by the brain. Adv Neurol 51:139-45
Miller, L G; Greenblatt, D J; Roy, R B et al. (1989) Dietary choline intake modulates benzodiazepine receptor binding and gamma-aminobutyric acidA receptor function in mouse brain. J Pharmacol Exp Ther 248:1-6
Wecker, L; Cawley, G; Rothermel, S (1989) Acute choline supplementation in vivo enhances acetylcholine synthesis in vitro when neurotransmitter release is increased by potassium. J Neurochem 52:568-75
Wecker, L (1988) Influence of dietary choline availability and neuronal demand on acetylcholine synthesis by rat brain. J Neurochem 51:497-504
Wuarin-Bierman, L; Wecker, L (1988) Choline supplementation increases serum alkaline phosphatase activity in rats. Clin Chim Acta 176:237-8

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