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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH033443-08
Application #
3375406
Study Section
(BPNA)
Project Start
1979-12-01
Project End
1989-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
8
Fiscal Year
1987
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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