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. 1991 Dec 15;88(24):11475–11479. doi: 10.1073/pnas.88.24.11475

Age-dependent decrease in the affinity of muscarinic M1 receptors in neocortex of rhesus monkeys.

M G Vannucchi 1, P S Goldman-Rakic 1
PMCID: PMC53158  PMID: 1763062

Abstract

In vitro autoradiography on tissue sections and receptor assay in cortical membrane homogenates revealed that pirenzepine high-affinity muscarinic sites (M1) decrease in affinity in the prefrontal cortex and in other cortical areas of aged rhesus monkey (Macaca mulatta). Carbachol competition experiments detected only a single, low-affinity class of sites in old monkeys, while two classes of sites (low and high affinity) were observed in young adults. The change in affinity in the aged monkeys is not accompanied by a decrease in the density of these sites and, further, the age-related decline in the affinity of the M1 site is reversible. In the presence of Mg2+, the M1 muscarinic receptors in the aged monkeys were capable of forming carbachol high-affinity sites. These results provide evidence for age-dependent functional changes in receptor activity in cerebral cortex and indicate that these receptors maintain a degree of plasticity that could be a strategic target for research aimed at treatment of memory disorders in aged humans.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Araujo D. M., Lapchak P. A., Meaney M. J., Collier B., Quirion R. Effects of aging on nicotinic and muscarinic autoreceptor function in the rat brain: relationship to presynaptic cholinergic markers and binding sites. J Neurosci. 1990 Sep;10(9):3069–3078. doi: 10.1523/JNEUROSCI.10-09-03069.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baker S. P., Marchand S., O'Neil E., Nelson C. A., Posner P. Age-related changes in cardiac muscarinic receptors: decreased ability of the receptor to form a high affinity agonist binding state. J Gerontol. 1985 Mar;40(2):141–146. doi: 10.1093/geronj/40.2.141. [DOI] [PubMed] [Google Scholar]
  3. Bartus R. T., Dean R. L., 3rd, Beer B., Lippa A. S. The cholinergic hypothesis of geriatric memory dysfunction. Science. 1982 Jul 30;217(4558):408–414. doi: 10.1126/science.7046051. [DOI] [PubMed] [Google Scholar]
  4. Bartus R. T., Fleming D., Johnson H. R. Aging in the rhesus monkey: debilitating effects on short-term memory. J Gerontol. 1978 Nov;33(6):858–871. doi: 10.1093/geronj/33.6.858. [DOI] [PubMed] [Google Scholar]
  5. Biegon A., Duvdevani R., Greenberger V., Segal M. Aging and brain cholinergic muscarinic receptors: an autoradiographic study in the rat. J Neurochem. 1988 Nov;51(5):1381–1385. doi: 10.1111/j.1471-4159.1988.tb01101.x. [DOI] [PubMed] [Google Scholar]
  6. Feldman R. D., Limbird L. E., Nadeau J., Robertson D., Wood A. J. Alterations in leukocyte beta-receptor affinity with aging. A potential explanation for altered beta-adrenergic sensitivity in the elderly. N Engl J Med. 1984 Mar 29;310(13):815–819. doi: 10.1056/NEJM198403293101303. [DOI] [PubMed] [Google Scholar]
  7. Flynn D. D., Mash D. C. Characterization of L-[3H]nicotine binding in human cerebral cortex: comparison between Alzheimer's disease and the normal. J Neurochem. 1986 Dec;47(6):1948–1954. doi: 10.1111/j.1471-4159.1986.tb13113.x. [DOI] [PubMed] [Google Scholar]
  8. Gibson G. E., Peterson C., Jenden D. J. Brain acetylcholine synthesis declines with senescence. Science. 1981 Aug 7;213(4508):674–676. doi: 10.1126/science.7256270. [DOI] [PubMed] [Google Scholar]
  9. Goldman-Rakic P. S., Lidow M. S., Gallager D. W. Overlap of dopaminergic, adrenergic, and serotoninergic receptors and complementarity of their subtypes in primate prefrontal cortex. J Neurosci. 1990 Jul;10(7):2125–2138. doi: 10.1523/JNEUROSCI.10-07-02125.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hammer R., Berrie C. P., Birdsall N. J., Burgen A. S., Hulme E. C. Pirenzepine distinguishes between different subclasses of muscarinic receptors. Nature. 1980 Jan 3;283(5742):90–92. doi: 10.1038/283090a0. [DOI] [PubMed] [Google Scholar]
  11. Hancock A. A., Bush E. N., Stanisic D., Kyncl J. J., Lin C. T. Data normalization before statistical analysis: keeping the horse before the cart. Trends Pharmacol Sci. 1988 Jan;9(1):29–32. doi: 10.1016/0165-6147(88)90239-8. [DOI] [PubMed] [Google Scholar]
  12. Hulme E. C., Berrie C. P., Birdsall N. J., Jameson M., Stockton J. M. Regulation of muscarinic agonist binding by cations and guanine nucleotides. Eur J Pharmacol. 1983 Oct 14;94(1-2):59–72. doi: 10.1016/0014-2999(83)90442-9. [DOI] [PubMed] [Google Scholar]
  13. Ingram D. K., London E. D., Goodrick C. L. Age and neurochemical correlates of radial maze performance in rats. Neurobiol Aging. 1981 Spring;2(1):41–47. doi: 10.1016/0197-4580(81)90058-0. [DOI] [PubMed] [Google Scholar]
  14. Landfield P. W. Hippocampal neurobiological mechanisms of age-related memory dysfunction. Neurobiol Aging. 1988 Sep-Dec;9(5-6):571–579. doi: 10.1016/s0197-4580(88)80116-7. [DOI] [PubMed] [Google Scholar]
  15. Lewis D. A. Distribution of choline acetyltransferase-immunoreactive axons in monkey frontal cortex. Neuroscience. 1991;40(2):363–374. doi: 10.1016/0306-4522(91)90126-9. [DOI] [PubMed] [Google Scholar]
  16. Lidow M. S., Gallager D. W., Rakic P., Goldman-Rakic P. S. Regional differences in the distribution of muscarinic cholinergic receptors in the macaque cerebral cortex. J Comp Neurol. 1989 Nov 8;289(2):247–259. doi: 10.1002/cne.902890206. [DOI] [PubMed] [Google Scholar]
  17. Lippa A. S., Loullis C. C., Rotrosen J., Cordasco D. M., Critchett D. J., Joseph J. A. Conformational changes in muscarinic receptors may produce diminished cholinergic neurotransmission and memory deficits in aged rats. Neurobiol Aging. 1985 Winter;6(4):317–323. doi: 10.1016/0197-4580(85)90010-7. [DOI] [PubMed] [Google Scholar]
  18. Mash D. C., White W. F., Mesulam M. M. Distribution of muscarinic receptor subtypes within architectonic subregions of the primate cerebral cortex. J Comp Neurol. 1988 Dec 8;278(2):265–274. doi: 10.1002/cne.902780209. [DOI] [PubMed] [Google Scholar]
  19. McCormick D. A., Prince D. A. Two types of muscarinic response to acetylcholine in mammalian cortical neurons. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6344–6348. doi: 10.1073/pnas.82.18.6344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Norman A. B., Blaker S. N., Thal L., Creese I. Effects of aging and cholinergic deafferentation on putative muscarinic cholinergic receptor subtypes in rat cerebral cortex. Neurosci Lett. 1986 Oct 8;70(2):289–294. doi: 10.1016/0304-3940(86)90479-9. [DOI] [PubMed] [Google Scholar]
  21. Pilch H., Müller W. E. Chronic treatment with choline or scopolamine indicates the presence of muscarinic cholinergic receptor plasticity in the frontal cortex of young but not of aged mice. J Neural Transm. 1988;71(1):39–43. doi: 10.1007/BF01259408. [DOI] [PubMed] [Google Scholar]
  22. Presty S. K., Bachevalier J., Walker L. C., Struble R. G., Price D. L., Mishkin M., Cork L. C. Age differences in recognition memory of the rhesus monkey (Macaca mulatta). Neurobiol Aging. 1987 Sep-Oct;8(5):435–440. doi: 10.1016/0197-4580(87)90038-8. [DOI] [PubMed] [Google Scholar]
  23. Rakic P., Goldman-Rakic P. S., Gallager D. Quantitative autoradiography of major neurotransmitter receptors in the monkey striate and extrastriate cortex. J Neurosci. 1988 Oct;8(10):3670–3690. doi: 10.1523/JNEUROSCI.08-10-03670.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rowe J. W., Kahn R. L. Human aging: usual and successful. Science. 1987 Jul 10;237(4811):143–149. doi: 10.1126/science.3299702. [DOI] [PubMed] [Google Scholar]
  25. Schroeder F. Role of membrane lipid asymmetry in aging. Neurobiol Aging. 1984 Winter;5(4):323–333. doi: 10.1016/0197-4580(84)90010-1. [DOI] [PubMed] [Google Scholar]
  26. Schwartz M. L., Goldman-Rakic P. S. Callosal and intrahemispheric connectivity of the prefrontal association cortex in rhesus monkey: relation between intraparietal and principal sulcal cortex. J Comp Neurol. 1984 Jul 1;226(3):403–420. doi: 10.1002/cne.902260309. [DOI] [PubMed] [Google Scholar]
  27. Selkoe D. J., Bell D. S., Podlisny M. B., Price D. L., Cork L. C. Conservation of brain amyloid proteins in aged mammals and humans with Alzheimer's disease. Science. 1987 Feb 20;235(4791):873–877. doi: 10.1126/science.3544219. [DOI] [PubMed] [Google Scholar]
  28. Spencer D. G., Jr, Horváth E., Traber J. Direct autoradiographic determination of M1 and M2 muscarinic acetylcholine receptor distribution in the rat brain: relation to cholinergic nuclei and projections. Brain Res. 1986 Aug 13;380(1):59–68. doi: 10.1016/0006-8993(86)91429-0. [DOI] [PubMed] [Google Scholar]
  29. Surichamorn W., Kim O. N., Lee N. H., Lai W. S., el-Fakahany E. E. Effects of aging on the interaction of quinuclidinyl benzilate, N-methylscopolamine, pirenzepine, and gallamine with brain muscarinic receptors. Neurochem Res. 1988 Dec;13(12):1183–1191. doi: 10.1007/BF00971637. [DOI] [PubMed] [Google Scholar]
  30. Vannucchi M. G., Casamenti F., Pepeu G. Decrease of acetylcholine release from cortical slices in aged rats: investigations into its reversal by phosphatidylserine. J Neurochem. 1990 Sep;55(3):819–825. doi: 10.1111/j.1471-4159.1990.tb04565.x. [DOI] [PubMed] [Google Scholar]
  31. Wagster M. V., Whitehouse P. J., Walker L. C., Kellar K. J., Price D. L. Laminar organization and age-related loss of cholinergic receptors in temporal neocortex of rhesus monkey. J Neurosci. 1990 Sep;10(9):2879–2885. doi: 10.1523/JNEUROSCI.10-09-02879.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Watson M., Roeske W. R., Yamamura H. I. [3H]pirenzepine and (-)-[3H]quinuclidinyl benzilate binding to rat cerebral cortical and cardiac muscarinic cholinergic sites. II. Characterization and regulation of antagonist binding to putative muscarinic subtypes. J Pharmacol Exp Ther. 1986 May;237(2):419–427. [PubMed] [Google Scholar]
  33. Wenk G. L., Pierce D. J., Struble R. G., Price D. L., Cork L. C. Age-related changes in multiple neurotransmitter systems in the monkey brain. Neurobiol Aging. 1989 Jan-Feb;10(1):11–19. doi: 10.1016/s0197-4580(89)80005-3. [DOI] [PubMed] [Google Scholar]

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