Our ability to understand and treat some behavioral disorders has benefitted greatly from our expanding knowledge about the biochemistry and pharmacology of monoamine neurotransmitters. Although abundant evidence indicates that brain acetylcholine (ACh) is also involved in behavioral diseases, much less basic information is available about this transmitter, and few if any drugs exists which can be given chronically to enhance cholinergic CNS transmission. Our proposal studies focus on a poorly- understood and perhaps-unique aspect of cholinergic neurons, i.e., their use of choline as a precursor for both ACh and such membrane phospholipids as phosphatidylcholine (PC; lecithin). We and others previously showed that supplemental choline could increase the syntheses of both ACh (particularly in frequently- firing neurons) and phosphocholine (an intermediate in PC synthesis). More recent studies have shown that the choline in neuronal PC is, in fact, used for ACh synthesis, and that, when choline is in short supply, the brain used it for this purpose preferentially, at the expense of membrane phospholipids. When superfused slices of rat striatum were depolarized repeatedly without adequate external choline, this PC was depleted, and most of its choline content would be accounted for by released ACh. Moreover, the other major membrane phospholipids, phosphatidylserine (PS) and phosphatidylethanolamine (PE), as well as membrane proteins, also were depleted, suggesting a relationship between neuronal depolarization and membrane levels. These reductions could all be blocked (and ACh release enhanced) by adding adequate choline to the medium. Moreover, choline's actions may be potentiated by cytidine or 4-aminopyridine, and its incorporation into neuronal PC enhanced by PS. Proposed studies examine the biochemical mechanisms, tissue distribution, and functional consequences of these changes in membrane phospholipids, using cholinergic cells lines (LAN-2; NG 108-15; PC-12), superfused rat brain slices, synaptosomes, and whole animals. We will also continue studies (on human brain samples) which suggest that related abnormalities occur in Alzheimer's disease, and will determine whether psychotropic drugs (which can cause tardive dyskinesia) affect PC metabolism in cholinergic neurons.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Method to Extend Research in Time (MERIT) Award (R37)
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Neurosciences Research Review Committee (BPN)
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Massachusetts Institute of Technology
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Wurtman, R J; Cansev, M; Ulus, I H (2009) Synapse formation is enhanced by oral administration of uridine and DHA, the circulating precursors of brain phosphatides. J Nutr Health Aging 13:189-97
Wurtman, Richard J; Cansev, Mehmet; Sakamoto, Toshimasa et al. (2009) Administration of docosahexaenoic acid, uridine and choline increases levels of synaptic membranes and dendritic spines in rodent brain. World Rev Nutr Diet 99:71-96
Cansev, Mehmet; Marzloff, George; Sakamoto, Toshimasa et al. (2009) Giving uridine and/or docosahexaenoic acid orally to rat dams during gestation and nursing increases synaptic elements in brains of weanling pups. Dev Neurosci 31:181-92
Wurtman, Richard J; Ulus, Ismail H; Cansev, Mehmet et al. (2006) Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally. Brain Res 1088:83-92
Ulus, Ismail H; Watkins, Carol J; Cansev, Mehmet et al. (2006) Cytidine and uridine increase striatal CDP-choline levels without decreasing acetylcholine synthesis or release. Cell Mol Neurobiol 26:563-77
Cansev, Mehmet (2006) Uridine and cytidine in the brain: their transport and utilization. Brain Res Rev 52:389-97
Pooler, Amy M; Xi, Shijun C; Wurtman, Richard J (2006) The 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor pravastatin enhances neurite outgrowth in hippocampal neurons. J Neurochem 97:716-23
Pooler, A M; Guez, D H; Benedictus, R et al. (2005) Uridine enhances neurite outgrowth in nerve growth factor-differentiated pheochromocytoma cells. Neuroscience 134:207-14
Cansev, Mehmet; Watkins, Carol J; van der Beek, Eline M et al. (2005) Oral uridine-5'-monophosphate (UMP) increases brain CDP-choline levels in gerbils. Brain Res 1058:101-8
Wurtman, Richard J (2005) Genes, stress, and depression. Metabolism 54:16-9

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