Oxidative Stress and the Loss of Receptor Sensitivity in Aging

  • J. A. Joseph
  • G. S. Roth
Part of the Advances in Behavioral Biology book series (ABBI, volume 44)


In this “decade of the brain” it is important to note that the U.S population is becoming older, and all the attendant age-related central neuronal alterations as well as correlative behavioral changes will be showing increases as well. By the year 2050 fully 30% of the total population will be over 65 years of age and there is a high probability that they will be exhibiting the most common behavioral alterations occurring in aging (i.e., decrements in motor and certain types of memory functions). Specifically, alterations in motor function may include decreases in balance, muscle strength and coordination, while memory deficits appear to occur primarily in secondary memory systems and are reflected in the retrieval of newly acquired information. Indeed, these characterizations have been supported by a great deal of research both in animals and humans. It should be evident that in cases of severe deficits in memory (e.g., Alzheimer’s Disease, AD) or motor function (Parkinson’s Disease, PD) during aging and in age-related diseases hospitalization and/or custodial care would be a likely outcome. This means that unless some means is found to reduce these decrements in neuronal function the health care costs will be staggering, and today’s costs will pale by comparison.


Kainic Acid GTPase Activity Receptor Sensitivity Striatal Slice Photosensitize Oxidation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adams, J.D. and Odun7P, I., 1991, Oxygen free radicals and parkinson’s disease, Free Rad. Biol. and Med. 10: 161.CrossRefGoogle Scholar
  2. Ainsworth, E.J., Fry, J.M., Brennan, P.C., Steamer, S.P., Rust, J.H., and Williamson, F.C., 1976, Life shortening, neoplasia and systematic injuries in mice after single or fractionated doses of neutron or gamma radiation, in: “Biological and Environmental Effects of Low-Level Radiation” IAEC, Vienna, AustriaGoogle Scholar
  3. Axelrod, J., Burch, R.M., and Jelsema, C.L., 1988, Recepto mediated activation of phospholipase A2 via GTP-binding protein arachidonic acid and its metabolites as second messengers, TINS, 11: 117.PubMedGoogle Scholar
  4. Bimbaumer, L, 1991, On the origins and present state of the art of G protein research, J. Recep. Res. 11: 577.Google Scholar
  5. Blake, M.J., Appel, N.M., Joseph, J.A., Stagg, C.A., Anson, M., De Souza, E.B. & Roth, G.S. 1991, Muscarinic acetylcholine receptor subtype mRNA expression and ligand binding in the aged rat brain, Neurobiol. Aging 12: 193.PubMedCrossRefGoogle Scholar
  6. Burnett, D.M., Daniell, L.C., and Zahniser, N.R., 1990, Decreased efficacy of inositol 1,4,5-trisphosphate to elicit calcium mobilization from cerebrocortical microsomes of aged rats Molec. Pharm. 37: 566.PubMedGoogle Scholar
  7. Carney, J.M., Starke-Reed, P.E., Oliver, C.N., Landum, R.W., Cheng, M.S., Wu, J.F., and Floyd, R.A. 1991, Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity and loss in temporal spatial member by chronic administration of the spin-trapping compound N-tent butyl-aphenylnitrone Proc. Natl. Acad. Sci. USA, 88: 3633.PubMedCrossRefGoogle Scholar
  8. Cadet, J.L., Lohr, J.B., and Jeste, D.V., 1986, Free radicals and tardive dyskinesia, TINS 9:107. Choi, D. W., 1987, Ionic dependence of glutamate neurotoxicity, J. Neurosci. 7: 369.Google Scholar
  9. Dawson, V.L., Dawson, T.M., Filloux, F.M. and Wamsley, J.K., 1988, Evidence for dopamine D-2 receptors on cholinergie intemeurons in the rat caudate putamen, Life Sci. 42: 1933.PubMedCrossRefGoogle Scholar
  10. Divac, I., Markowitsch, H.J., and Pritzel, M., 1978, Behavioral and anatomic consequences of small intrastriatal injections of kainic acid in the rat, Brain Res. 151: 523.PubMedCrossRefGoogle Scholar
  11. Favit, A., Nicoletti, F., Scapagnini, U., and Canonico, P.L., 1991, Ubiquinone protects cerebellar granule cells against glutamate-induced cytotoxicity, Soc. for Neurosci. Abs. 17: 791.Google Scholar
  12. Fields, J.Z., Reisine, T.D., and Yamamura, H.I., 1978 Loss of striatal dopaminergic receptors after intrastriatal kainic acid injection, Life Sci. 23: 569.PubMedCrossRefGoogle Scholar
  13. Fisher, S.K. Heacock, A.M., and B.W. Agranoff, B.W., 1992, Inositol lipids and signal transduction in the nervous system: an update, J. Neurochem. 58: 18.Google Scholar
  14. Flynn, D.D., Weinstein, D.A., and Mash, D.C., 1991, Loss of high affinity agonist binding to M1 muscarinic receptors in Alzheimer’s disease: Implications for the failure of cholinergic replacement therapy, Ann. Neurol. 29: 256.Google Scholar
  15. Girotti, A.W., 1992, Photosensitized oxidation of cholesterol in biological systems: reaction pathways, cytotoxic effects and defense mechanisms, J. Potochem. Photobio. 13: 105.CrossRefGoogle Scholar
  16. Grimes, J.D., Hassan, M.N., and Thakar, J., 1987 Antioxidant therapy in Parkinson’s disease, Can. J. Neurol. Sci. 14 (3 Supplement): 483.PubMedGoogle Scholar
  17. Halliwell, B. and Gutteridge J.M.C. 1989, Free Radicals in Biology and Medicine, Clarendon Press, Oxford, England.Google Scholar
  18. Harman, D., 1981, The aging process, PNAS USA 78: 7124.CrossRefGoogle Scholar
  19. Henry, J., and Roth, G.S. 1986, Modulation of rat striatal membrane fluidity: effects on age-related differences in dopamine receptor concentrations, Life Sci. 39: 1223.PubMedCrossRefGoogle Scholar
  20. Heron, D.S., Israeli, M., Hershkowitz, M., and Samuel, D., 1980 Lipid fluidity markedly modulates the binding of serotonin to mouse brain membranes, PNAS USA, 77: 7463.Google Scholar
  21. Joseph J.A. and Roth, G.S., 1988, Upregulation of striatal dopamine receptors and improvement of motor performance in senescence, in: “Central Determinants of Age Related Declines in Motor Function”, Annals of the New York Academy of Sciences Volume 515“, J.A. Joseph ed., New York Academy of Sciences, New York, NY.Google Scholar
  22. Joseph, J. A., Dalton, T.K. and Hunt, W.A., 1988a, Age-related decrements in the muscarinic enhancement of K*-evoked release of endogenous striatal dopamine: An indicator of altered cholinergicdopaminergic reciprocal inhibitory control in senescence, Brain Res. 454: 140.PubMedCrossRefGoogle Scholar
  23. Joseph, J.A., Dalton, T.K., Roth, G.S., and Hunt, W.A. 1988b. Alterations in muscarinic control of striatal dopamine autoreceptors in senescence: a deficit at the ligand-muscarinic receptor interface? Brain Res. 454: 149.PubMedCrossRefGoogle Scholar
  24. Joseph, J. A. and Roth, G.S., 1991, Loss of agonist receptor efficacy in senescence: Possible decrements in second messenger function and calcium mobilization. in: “Challenges in Aging: The 1990 Sandoz Lectures in Gerontology” M. Bergener, M. Ermini, and H.B. Stahelin, eds., Academic Press, New York, NY.Google Scholar
  25. Joseph, J.A., Kowatch, M.A., Maki, T., and Roth, G.S. 1991a, Selective cross activation /inhibition of second messenger systems and the reduction of age-related deficits in the muscarinic control of dopamine release from perifused rat striata, Brain Res. 537: 40.CrossRefGoogle Scholar
  26. Joseph, J.A., Yamagami, K., and Roth, G.S., 199lb, Loss of muscarinic responsiveness in senescence may be the result of decreased membrane fluidity, Soc. for Neurosci Abs. 17: 53.Google Scholar
  27. Joseph, J.A., Gupta, M., Han, Z., and Roth, G.S., 1991c, The deleterious effects of aging and kainic acid may be selective for the same striatal neuronal population and may share a common mechanism, Aging, 3: 361.PubMedGoogle Scholar
  28. Joseph, J.A., Hunt, W.A., Rabin, B.M. and Dalton, T.K. 1992, Possible “accelerated striatal aging” induced by 56Fe heavy particle irradiation: Implications for manned space flights, Radiation Res. 130: 88.PubMedCrossRefGoogle Scholar
  29. Joseph, J.A., Hunt, W.A., Rabin, B.M. and Dalton, T.K., 1993, Deficits in the sensitivity of striatal muscarinic receptors induced by ‘Fe heavy particle irradiation: Further “age-radiation parallels,” Radiation Res. 135: 257.Google Scholar
  30. Joseph, J. A., Villalobos-Molina, R., Rabin, B., Dalton, T., Harris, A., and Kandasamy, S., Reductions of 9Fe heavy particle irradiation-induced deficits in striatal muscarinic receptor sensitivity by selective cross activation/inhibition of second messenger systems, Rad. Res.,in press.Google Scholar
  31. Lafon-Cazal, M., Pietre S., Culasi, M., and Bockaert J., 1993, NMDA-dependent superoxide production and neurotoxicity, Nature 364: 535.PubMedCrossRefGoogle Scholar
  32. Lyons, W.E., Puttfarcken, P.S., and Coyle, J.T., 1991, Protection against kainic acid toxicity with lipophilic antioxidants in cerebellar granule cell cultures, Soc. for Neurosci. Abs. 17: 785.Google Scholar
  33. Mesco, E.R. Joseph, J.A., Blake, M.J., and Roth, G.S., 1991, Loss of D2 receptors during aging is partially due to decreased levels of mRNA, Brain Res. 545: 355.Google Scholar
  34. Mesco, E.R., Joseph, J.A., and Roth, G.S., 1992, Selective susceptibility of cultured striatal neurons to kainic acid, J. Neurosci Res. 31: 341.PubMedCrossRefGoogle Scholar
  35. Mesco, E.R., Carlson, S.G., Joseph, J.A., and Roth, G.S., 1993, Synthetic rate of D2-dopamine receptor mRNA is selectively reduced during aging, Mol. Brain Res. 17: 160.PubMedCrossRefGoogle Scholar
  36. Missiaen, L. Taylor, C.W., and Berridge, M.J., 1991, Spontaneous calcium release from inositol trisphosphate-sensitive calcium stores, Nature 352: (6332): 242.Google Scholar
  37. Morgan, D.G., 1987, The dopamine and serotonin systems during aging in human and rodent brain. A brief review., Prog Neuropsychopharm. Biol. Psych. 11: 153.CrossRefGoogle Scholar
  38. Murphy, T.H., Schnaar, R.L., and Coyle, J.T., 1990, Immature cortical neurons are uniquely sensitive to glutamate toxicity by inhibition of cystine uptake. FASEB J. 3: 1624.Google Scholar
  39. Scatton, B., 1982, Further evidence for the involvement of D2 but not DI dopamine receptors in dopaminergic control of striatal cholinergic transmission, Life Sci. 31: 2882.Google Scholar
  40. Schroeder, F., 1984 Role of membrane lipid asymmetry in aging, Neurobiol. Aging 5: 323.PubMedCrossRefGoogle Scholar
  41. Shinitzky, M. Heron, D.S., and Samuel, D., 1983, Restoration of membrane fluidity and serotonin receptors in aged mouse brain. in: “Aging of the Brain” Vol. 22“, D. Samuel, S., Algeri, S. Gershon, V.E. Grimm, and G. Tofano eds., Raven Press, New York.Google Scholar
  42. Smith, C.J., Perry, E.K., Perry, R.H., Fairbaim, A.F., and N.J.M Birdsall, A.F., 1987, Guanine nucleotide modulation of muscarinic cholinergic receptor binding in postmortem human brain a preliminary study in Alzheimer’s disease, Neurosci. Let. 82: 227.Google Scholar
  43. Stark, G., 1991, The effect of ionizing radiation on lipid membranes, Biochim. Biophys. Acta 1071: 103.PubMedCrossRefGoogle Scholar
  44. Stoof, J.C., De Boer, T., Smina, P., and Mulder, A.H., 1982, Stimulation of D2-dopamine receptors in rat neostriatum inhibits the release of acetylcholine and dopamine but does not affect the release of gammaaminobutryic acid, glutamate or serotonin, Eur. J. Pharmacol. 84: 211.PubMedCrossRefGoogle Scholar
  45. Upton, A.C., 1959, Ionizing radiation and aging. Gerontologia, 4: 162.CrossRefGoogle Scholar
  46. Vedova, F.D., Fumagalli, F., Sachetti, G., Racagni, G., and Brunello, N, 1992, Age-related variations in relative abundance of alternative spliced receptor mRNA’s in brain areas of two rat strains, Mol. Brain Res. 12: 357.PubMedCrossRefGoogle Scholar
  47. Villalobos-Molina, R., Joseph, J.A., Rabin, B., Kandasamy, S., Dalton, T.K., and Roth, G.S., ~Fe irradiation diminishes muscarinic but not alpha-1 adrenergic stimulated low Km GTPase in rat brain, Radial. Res.,submitted. Google Scholar
  48. Warpman, U., Alafuzoff, I., and Nordberg, A., 1993, Couupling of muscarinic receptors to GTP proteins in postmortem human brain-alterations in Alzheimer’s disease, Neurosci. Let. 150: 39.CrossRefGoogle Scholar
  49. Yamagami, K., Joseph, J.A., and Roth, G.S., 1991, Decreased concentrations of striatal muscarinic receptors and age-related decrement in muscarinic enhancement of K’-evoked release of endogenous dopamine, Neurobiol. Aging 13: 51.CrossRefGoogle Scholar
  50. Yamagami, K., Joseph, J.A., and Roth, G.S., 1992, Decrement of muscarinic receptor-stimulated low Km GTPase activity in striata and hippocampus from aged rat, Brain Res. 576: 327.PubMedCrossRefGoogle Scholar
  51. Zhu, X-Z, and Luo, L-G., 1992, Effect of nitroprusside (nitric oxide) on endogenous dopamine release from rat striatal slices, J. Neurochem. 59: 932.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • J. A. Joseph
    • 1
  • G. S. Roth
    • 2
  1. 1.USDA Human Nutrition Research Center on Agingat Tufts UniversityBostonUSA
  2. 2.Gerontology Research Center/NIABaltimoreUSA

Personalised recommendations