Dietary uridine-5′-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats
Membrane phospholipids like phosphatidylcholine (PC) are required for cellular growth and repair, and specifically for synaptic function. PC synthesis is controlled by cellular levels of its precursor, cytidine-5′-diphosphate choline (CDP-choline), which is produced from cytidine triphosphate (CTP) and phosphocholine. In rat PC12 cells exogenous uridine was shown to elevate intracellular CDP-choline levels, by promoting the synthesis of uridine triphosphate (UTP), which was partly converted to CTP. In such cells uridine also enhanced the neurite outgrowth produced by nerve growth factor (NGF). The present study assessed the effect of dietary supplementation with uridine-5′-monophosphate disodium (UMP-2Na+, an additive in infant milk formulas) on striatal dopamine (DA) release in aged rats. Male Fischer 344 rats consumed either a control diet or one fortified with 2.5% UMP for 6 wk, ad libitum. In vivo microdialysis was then used to measure spontaneous and potassium (K+)-evoked DA release in the right striatum. Potassium (K+)-evoked DA release was significantly greater among UMP-treated rats, i.e., 341±21% of basal levels vs. 283 ± 9% of basal levels in control rats (p<0.05); basal DA release was unchanged. In general, each animal’s K+-evoked DA release correlated with its striatal DA content, measured postmortem. The levels of neurofilament-70 and neurofilament-M proteins, biomarkers of neurite outgrowth, increased to 182±25% (p<0.05) and 221 ± 34% (p<0.01) of control values, respectively, with UMP consumption. Hence, UMP treatment not only enhances membrane phosphatide production but also can modulate two membrane-dependent processes, neurotransmitter release and neurite outgrowth, in vivo.
Index EntriesMicrodialysis dopamine neurite outgrowth nucleoside CDP-choline
Agut J., Lopez G-Coviella I., Ortiz J. A., and Wurtman R. J. (1993) Oral cytidine 5′-diphosphate choline administration to rats increases brain phospholipid levels. Ann. N. Y. Acad. Sci.
, 318–320.PubMedCrossRefGoogle Scholar
Agut J., Ortiz J. A., and Wurtman R. J. (2000) Cytidine-5′-diphosphocholine modulates dopamine K+-evoked release in striatum measured by microdialysis. Ann. N. Y. Acad. Sci.
, 332–335.PubMedCrossRefGoogle Scholar
Araki W. and Wurtman R. J. (1997) Control of membrane phosphatidylcholine biosynthesis by diacylglycerol levels in neuronal cells undergoing neurite outgrowth. Proc. Natl. Acad. Sci. U. S. A.
, 11946–11950.PubMedCrossRefGoogle Scholar
Araki W. and Wurtman R. J. (1998) How is membrane phospholipid biosynthesis controlled in neural tissues? J. Neurosci. Res.
, 667–674.PubMedCrossRefGoogle Scholar
Cansev M., Modyanova N. N., Watkins C. J., and Wurtman R. J. (2004) Oral uridine-5-monophosphate (UMP) elevates brain CDP-choline and improves spatial memory in gerbils. Thirty-fourth Neuroscience Meeting Abstract, 435.15.Google Scholar
Cornford E. M. and Oldendorf W. H. (1975) Independent blood-brain barrier transport systems for nucleic acid precursors. Biochim. Biophys. Acta
, 211–219.PubMedCrossRefGoogle Scholar
Gasser T., Moyer J. D., and Handschumacher R. E. (1981) Novel single-pass exchange of circulating uridine in rat liver. Science
, 777,778.PubMedCrossRefGoogle Scholar
Goldberg J. L. (2003) How does an axon grow? Genes Dev.
, 941–958.PubMedCrossRefGoogle Scholar
Grafstein B. and Forman D. S. (1980) Intracellular transport in neurons. Physiol. Rev.
, 1167–1283.PubMedGoogle Scholar
Kaasinen V. and Rinne J. O. (2002) Functional imaging studies of dopamine system and cognition in normal aging and Parkinson’s disease. Neurosci. Biobehav. Rev.
, 785–793.PubMedCrossRefGoogle Scholar
Kametani H., Iijima S., Spangler E. L., Ingram D. K., and Joseph J. A. (1995) In vsivo assessment of striatal dopamine release in the aged male Fischer 344 rat. Neurobiol. Aging
, 639–646.PubMedCrossRefGoogle Scholar
Kennedy E. P. and Weiss S. B. (1956) The function of cytidine coenzymes in the biosynthesis of phospholipids. J. Biol. Chem.
, 193–214.PubMedGoogle Scholar
Krugel U., Kittner H., Franke H., and Illes P. (2001) Stimulation of P2 receptors in the ventral tegmental area enhances dopaminergic mechanisms in vivo. Neuropharmacology
, 1084–1093.PubMedCrossRefGoogle Scholar
Lee V., Trojanowski J. Q., and Schlaepfer W. W. (1982) Induction of neurofilament triplet proteins in PC12 cells by nerve growth factor. Brain Res.
, 169–180.PubMedCrossRefGoogle Scholar
Paxinos G. and Watson C. (1986) The Rat Brain in Stereotaxic Coordinates, 2nd ed., Academic Press, San Diego, CA.Google Scholar
Pizzorno G., Cao D., Leffert J. J., Russell R. L., Zhang D., and Handschumacher R. E. (2002) Homeostatic control of uridine and the role of uridine phosphorylase: a biological and clinical update. Biochim. Biophys. Acta
, 133–144.PubMedGoogle Scholar
Pooler A. M., Guez D. H., Benedictus R., and Wurtman R. J. (2004) Uridine enhances neurite outgrowth in NGF-differentiated PC12 cells. Neuroscience
, in press.Google Scholar
Richardson U. I., Watkins C. J., Pierre C., Ulus I. H., and Wurtman R. J. (2003) Stimulation of CDP-choline synthesis by uridine or cytidine in PC12 rat pheochromocytoma cells. Brain Res.
, 161–167.PubMedCrossRefGoogle Scholar
Shoji-Kasai Y., Itakura M., Kataoka M., Yamamori S., and Takahashi M. (2002) Protein kinase C-mediated translocation of secretory vesicles to plasma membrane and enhancement of neurotransmitter release from PC12 cells. Eur. J. Neurosci.
, 1390–1394.PubMedCrossRefGoogle Scholar
Sivasankaran R., Pei J., Wang K. C., Zhang Y. P., Shields C. B., Xu X. M., and He Z. (2004) PKC mediates inhibitory effects of myelin and chondroitin sulfate proteoglycans on axonal regeneration. Nat. Neurosci.
, 261–268.PubMedCrossRefGoogle Scholar
Sonoda T. and Tatibana M. (1978) Metabolic fate of pyrimidines and purines in dietary nucleic acids ingested by mice. Biochim. Biophys. Acta
, 55–66.PubMedGoogle Scholar
Wang L., Osborne P. G., Yu X., Shangguan D., Zhao R., Han H., and Liu G. (2003) Hyperoxia caused by microdialysis perfusion decreased striatalmonoamines: involvement of oxidative stress. Neurochem. Int.
, 465–470.PubMedCrossRefGoogle Scholar
Weiss G. B. (1995) Metabolism and actions of CDP-choline as an endogenous compound and administered exogenously as citicoline. Life Sci.
, 637–660.PubMedCrossRefGoogle Scholar
Wurtman R. J., Regan M., Ulus I., and Yu L. (2000) Effect of oral CDP-choline on plasma choline and uridine levels in humans. Biochem. Pharmacol.
, 989–992.PubMedCrossRefGoogle Scholar
Yurek D. M., Hipkens S. B., Hebert M. A., Gash D. M., and Gerhardt G. A. (1998) Age-related decline in striatal dopamine release and motoric function in Brown Norway/Fischer 344 hybrid rats. Brain Res.
, 246–256.PubMedCrossRefGoogle Scholar