The function of the NMDA-receptor during normal brain aging

  • W. E. Müller
  • S. Stoll
  • K. Scheuer
  • A. Meichelböck
Conference paper
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 44)


Age-related changes of N-methyl-D-aspartate (NMDA) receptors have been found in cortical areas and in the hippocampus of many species. On the basis of a variety of experimental observations it has been suggested that the decrease of NMDA-receptor density might be one of the causative factors of the cognitive decline with aging. Based on these findings several strategies have been developed to improve cognition by compensating the NMDA-receptor deficits in aging. The most promising approaches are the indirect activation of glutamatergic neurotransmission by agonists of the glycine site or the restoration of the age-related deficit of receptor density by several nootropics.


NMDA Receptor Membrane Fluidity Passive Avoidance NMDA Antagonist Aged Animal 
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  1. Baskys A, Reynolds JM, Carlen PL (1990) NMDA depolarizations and long-term potentation are reduced in the aged rat neocortex. Brain Res 530: 142–146PubMedCrossRefGoogle Scholar
  2. Cimino M, Vantinin G, Algeri S, Curatola G, Pezzoli C, Stramentinoli G (1984) Age- related modification of dopaminergic and ß-adrenergic receptor system: restoration to normal activity by modifying membrane fluidity with S-adenosylmethionine. Life Sci 34: 2029–2039PubMedCrossRefGoogle Scholar
  3. Cohen SA, Müller WE (1992) Age-related alterations of NMDA-receptor properties in the mouse forebrain: partial restoration by chronic phosphatidylserine treatment. Brain Res 584: 174–180PubMedCrossRefGoogle Scholar
  4. Cohen SA, Müller WE (1993) Effects of piracetam on N-methyl-D-asparate receptor properties in the aged mouse brain. Pharmacology 47: 217–222PubMedCrossRefGoogle Scholar
  5. Collingridge G (1987) The role of NMDA receptors in learning and memory. Nature 330: 604–608PubMedCrossRefGoogle Scholar
  6. Davis JL, Klood JS (1987) Excitatory amino acids and memory processing. Soc Neurosci Abstr 13: 658Google Scholar
  7. Davis S, Markowska AL, Wenk GL, Barnes CA (1993) Acetyl-L-carnitine: behavioral, electrophysiological, and neurochemical effects. Neurobiol Aging 14: 107–115PubMedCrossRefGoogle Scholar
  8. Deutsch SI, Moruhisa JM (1988) Glutamatergic abnormalities in Alzheimer’s disease and a rationale for clinical trials with L-glutamate. Clin Neuropharmacol 1: 11–35Google Scholar
  9. Fiore L, Rampello L (1989) L-Acetylcarnitine attenuates the age-dependent decrease of NMDA-sensitive glutamate receptors in rat hippocampus. Acta Neurol 11: 346–351Google Scholar
  10. Fishkin RJ, Ince ES, Carlezon Jr WA, Dunn RW (1993) D-cycloserine attentuates scopolamine-induced learning and memory deficits in rats. Behav Neural Biol 59: 150–157PubMedCrossRefGoogle Scholar
  11. Gonzales RA, Brown LM, Jones TW, Trent RD, Westbrook SL, Leslie SW (1991) N-methyl-D-asparate mediated respones decrease with age in Fischer 344 rat brain. Neurobiol Aging 12: 219–225PubMedCrossRefGoogle Scholar
  12. Hartmann H, Cohen SA, Müller WE (1993) Effects of subchronic administration of pyritinol on receptor deficits and phosphatidylinositol metabolism in the brain of the aged mouse. Neuropharmacology 32: 119–125PubMedCrossRefGoogle Scholar
  13. Henry JM, Roth GS (1986) Modulation of rat striatal membrane fluidity: effects on age related differences in dopamine receptor concentrations. Life Sei 39: 1223–1229CrossRefGoogle Scholar
  14. Ingram DK, Garofalo P, Spangler EL, Mantione CR, Odano I, London ED (1992) Reduced density of NMDA receptors and increased sensitivity to Dizocilpine- induced learning impairment in aged rats. Brain Res 580: 273–280PubMedCrossRefGoogle Scholar
  15. Jablonka B, Schindler U (1990) Changes of strychnine-insensitive glycine sites in the hippocampus of senescent rats. Eur J Pharmacol 183: 476–477CrossRefGoogle Scholar
  16. Javitt DC, Zukin SR (1989) Biexponential kinetics of 3H-MK-801 binding: evidence for access to closed and open N-methyl-D-asparate receptor channels. Mol Pharmacol 35: 378–393Google Scholar
  17. Joseph JA, Yamagami K, Roth GS (1991) Loss of muscarinic responsiveness in senscence may be the result of decreased membrane fluidity. Soc Neurosci Abstr 17: 53Google Scholar
  18. Jones RW, Schaeffer CL, DeNoble VJ (1989) Systemically administrated N-methyl- D-asparate interferes with acquisition of a passive avoidance response in rats. Pharmacol Biochem Behav 34: 181–185PubMedCrossRefGoogle Scholar
  19. Jones RW, Wesnes KA, Kirby J (1991) Effects of NMDA modulation in scopolamine dementia. Ann NY Acad Sei 640: 241–244Google Scholar
  20. Keller EA, Borghese CM, Carrer HF, Ramirez OA (1992) The learning capacity of high or low performance rats is related to the hippocampus NMDA receptors. Brain Res 576: 162–164PubMedCrossRefGoogle Scholar
  21. Kitamura Y, Zhao XH, Ohnuki T, Makiko T, Nomura Y (1992) Age-related changes in transmitter glutamate and NMDA receptor/channels in the brain of senescence-accelerated mouse. Neuroscience 137: 169–172Google Scholar
  22. Kornhuber J, Mack-Burkhardt F, Konradi C, Fritze J, Riederer P (1989) Effect of antemortem and postmortem factors on 3H-MK-801 binding in the human brain: transient elevation during early childhood. Life Sci 45: 745–749PubMedCrossRefGoogle Scholar
  23. Lakowicz JR (1983) Principles of fluorescence spectroscopy. Plenum Press, New YorkGoogle Scholar
  24. Lowry O, Rosenbrough NI, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193: 265–275PubMedGoogle Scholar
  25. Morris RGM, Anderson E, Lynch G, Baudry M (1986) Selective impairment of learning and blockade of long-term potentation by an N-methyl-D-asparate receptor antagonist, AP5. Nature 319: 774–776PubMedCrossRefGoogle Scholar
  26. Morris RGM (1989) Synaptic plasticity and learning: selective impairment of learning in rats and blockade of long-term potentation in vivo by the N-methyl-D-asparate receptor antagonist AP5. J Neurosci 9: 3040–3057PubMedGoogle Scholar
  27. Monahan JB, Handelmann GE, Hood WF, Cordi AA (1989) D-cycloserine, a positive modulator of the N-methyl-D-asparate receptor, enhances performance of learning tasks in rats. Pharmacol Biochem Behav 34: 649–653PubMedCrossRefGoogle Scholar
  28. Muccioli G, Scordamaglia A, Bertacco S, Di Carlo R (1992) Effect of S-adenosyl-L-methionine on brain muscarinic receptors of aged rats. Eur J Pharmacol 227: 293–299PubMedCrossRefGoogle Scholar
  29. Munson P, Rodbard D (1980) Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem 107: 220–239PubMedCrossRefGoogle Scholar
  30. Ogawa N, Mizukawa K, Haba K, Asanuma M, Mori A (1992) Effects of chronic bifemelane hydrochloride administration on receptors for N-methyl-D-asparate in the aged-rat brain. Neurochem Res 17: 687–691PubMedCrossRefGoogle Scholar
  31. Palmer AM (1991) Excitatory amino acid neurons and receptors in Alzheimer’s disease. In: Kozilowski AP, Barrinuevo G (eds) Neurobiology of the NMDA receptor. VCH, New York, pp 203–237Google Scholar
  32. Palmer AM, Gershon S (1990) Is the neuronal basis of Alzheimer’s disease cholinergic or glutamatergic? FASEB J 4: 2745–2752Google Scholar
  33. Parada-Turska J, Turski WA (1990) Excitatory amino acid antagonists and memory: effect of drugs acting at N-methyl-D-aspartate receptors in learning and memory tasks. Neuropharmacology 29: 1111–1116PubMedCrossRefGoogle Scholar
  34. Pelleymounter MA, Beatty G, Gallagher M (1990) Hippocampal 3H-CPP binding and spatial learning deficits in aged rats. Psychobiology 18: 298–304Google Scholar
  35. Peterson C, Cotman CW (1989) Strain-dependent decrease in glutamate binding to the N-methyl-D-aspartatic acid receptor during aging. Neurosci Lett 104: 309–313PubMedCrossRefGoogle Scholar
  36. Pigott MA, Perry EK, Perry RH, Court JA (1992) 3H-MK-801 binding to the NMDA- receptor complex, and its modulation in human frontal cortex during development and aging. Brain Res 588: 277–286Google Scholar
  37. Pittaluga A, Fedele E, Risiglione C, Raiteri M (1993) Age-related decrease of the NMDA receptor-mediated noradrenaline release in rat hippocampus and partial restoration by D-cycloserine. Eur J Pharmacol 231: 129–134PubMedCrossRefGoogle Scholar
  38. Reynolds IJ, Murphy SN, Miller RJ (1987) 3H-labeled MK-801 binding to the excitatory amino acid receptor complex from rat brain is enhanced by glycine. Proc Natl Acad Sei USA 84: 7744–7748Google Scholar
  39. Scheuer K, Stoll S, Paschke U, Weigel R, Müller WE (1994) NMDA receptor density and membrane fluidity as major determinats of the cognitive decline in aging. Pharmacol Biochem Behav (submitted)Google Scholar
  40. Spangler EL, Bresnahan EL, Garofalo P, Muth NJ, Heller B, Ingram DK (1991) NMDA receptor channel antagonism by dizocilipine (MK-801) impairs performance of rats in aversively motivated complex maze tasks. Pharmacol Biochem Behav 40: 949–958PubMedCrossRefGoogle Scholar
  41. Straubli U, Lynch G (1990) NMDA receptors and memory: evidence from pharmacological and correlational studies. In: Kozikowski AP, Barrionuevo G (eds) Neurobiology of the NMDA receptor. VCH, New York, pp 129–148Google Scholar
  42. Tamaru M, Yoneda Y, Ogita K, Shimizu J, Nagata Y (1991) Age-related decreases of the N-methyl-D-asparate receptor complex in the rat cerebral cortex and hippocampus. Brain Res 542: 83–90PubMedCrossRefGoogle Scholar
  43. Venable N, Kelly PH (1980) Effect of NMDA-receptor antagonists on passive avoidance learning and retrieval in rats and mice. Neurobiol Aging 1: 59–63CrossRefGoogle Scholar
  44. Vogel W, Broverman DM, Draguns JG (1966) The role of glutamic acid in cognitive behaviors. Psychol Bull 65: 367–382PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • W. E. Müller
    • 1
  • S. Stoll
    • 1
  • K. Scheuer
    • 1
  • A. Meichelböck
    • 1
  1. 1.Department of PsychopharmacologyCentral Institute of Mental HealthMannheimFederal Republic of Germany

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