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Metrifonate effects on acetylcholine and biogenic amines in rat cortex

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Abstract

The effect of systemic and local administration of metrifonate (MTF), a long-acting cholinesterase inhibitor (ChEl) on extracellular levels of acetylcholine (ACh), norepinephrine (NE), dopamine (DA) and serotonin (5-HT) was investigated in the rat cortex by using transcortical microdialysis. Metrifonate (20, 40, and 80 mg/kg, s.c.) increased ACh levels in a dose-dependent manner above the baseline. Two consecutive administrations (80 mg/kg) enhanced ACh levels producing two similar patterns of elevation. A significant increase in NE was also seen at 80 mg/kg. Systemic administration (20 mg/kg) of MTF produced a significant increase of DA levels. Local cortical perfusion of MTF through the probe caused a significant but slow increase of ACh as well as an increase of NE levels. Compared to NE, the elevation of DA was more rapid and more longlasting. The cortical levels of 5-HT were not modified by MTF given by either route. These results support the concept of MTF being a potential drug for treatment of Alzheimer disease (AD).

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References

  1. Terry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., Hansen, L. A., and Katzman, R. 1991. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30:572–580.

    Google Scholar 

  2. DeKosky, S. T., Styren, S. D., and O'Malley, M. E. 1994. Cholinergic changes and synaptic alterations in Alzheimer's disease. Pages 93–97,in Giacobini, E., and Becker R. (eds), Alzheimer Disease: Therapeutic Strategies, Birkhauser Boston, Cambridge.

    Google Scholar 

  3. Giacobini, E. 1993. Pharmacotherapy of Alzheimer's disease: New drugs and novel strategies. Pages 529–538,in Corain, B., Iqbal, K., Nicolini, M., Winblad, B., Wisniewski, H., and Zatta, P. (eds), Alzheimer's Disease: Advances in Clinical and Basic Research, John Wiley & Sons Ltd, New York.

    Google Scholar 

  4. Giacobini, E., and Cuadra, G. 1994. Second and third generation cholinesterase inhibitors: from preclinical studies to clinical efficacy. Pages 155–171,in Giacobini, E., and Becker, R. (eds), Alzheimer Disease: Therapeutic Strategies, Birkhauser Boston, Cambridge.

    Google Scholar 

  5. Nordgren, I., Bengston, E., Holmstedt, B., and Petterson, B. M. 1981. Levels of metrifonate and dichlorvos in plasma and erythrocytes during treatment of schistosomiasis with Bilarcil. Acta Pharmacol. Toxicol. 48:79–86.

    Google Scholar 

  6. Hallak, M., and Giacobini, E. 1987. A comparison of the effects of two inhibitors on brain cholinesterase. Neuropharmacology 26(6):521–530.

    Google Scholar 

  7. Hallak, M., and Giacobini, E. 1989. Physostigmine, tacrine and metrifonate: The effect of multiple doses on acetylcholine metabolism in rat brain. Neuropharmacology 28(3):199–206.

    Google Scholar 

  8. Nordgren, I., Karlen, B., and Kimland, M. 1992. Metrifonate and tacrine: A comparative study on their effect on acetylcholine dynamics in mouse brain. Pharmacol. Toxicol. 71:236–240.

    Google Scholar 

  9. Becker, R. E., Colliver, J., Elble, R., Feldman, E., Giacobini, E., Kumar, V., Markwell, S., Moriearty, P., Parks, R., Shillcutt, S. D., Unni, L., Vicari, S., Womack, C., and Zec, R. F. 1990. Effects of metrifonate, a long-acting cholinesterase inhibitor, in Alzheimer disease: Report of an open trial. Drug Dev. Res. 19:425–434.

    Google Scholar 

  10. Hardy, J., Adolfsson, R., Alafuzoff, I., Bucht, G., Marcusson, J., Nyberg, P., Perdhal, E., Wester, P., and Winblad, B. 1985. Transmitter deficits in Alzheimer's disease. Neurochem. Int. 7:545–563.

    Google Scholar 

  11. Decker, M. W., and McGaugh, J. L. 1991 The role of interactions between cholinergic system and other neuromodulatory systems in learning and memory. Synapse 7:151–178.

    Google Scholar 

  12. Mesulam, M. M., and Geula, C. 1988. Nucleus basalis (Ch4) and cortical cholinergic innervation in the human brain: Observation based on the distribution of acetylcholinesterase and choline acetyltransferase. J. Comp. Neurol. 275:216–240.

    Google Scholar 

  13. Parnavelas, J. C. 1990. Neurotransmitters in the cerebral cortex. Pages 13–29,in Uylings, H. B. M., Van Eden, C. G., De Bruin, J. P. C., Corner, M. A., and Feenstra, M. G. P.,in Progress in Brain Research, Vol. 85, Elsevier, The Netherlands.

    Google Scholar 

  14. Vanderwolf, C. H. 1987. Near-total loss of “learning” and “memory” as a result of combined cholinergic and serotoninergic blockade in the rat. Behav. Brain Res. 23:43–57.

    Google Scholar 

  15. Arnsten, A. F. T., and Goldman-Rakic, P. S. 1985. 2-Adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science 230:1273–1276.

    Google Scholar 

  16. Sara, S. J. 1989. Noradrenergic-cholinergic interaction: Its possible role in memory dysfunction associated with senile dementia. Arch. Gerontol. Geriatr. (Suppl. 1):99–108.

    Google Scholar 

  17. Day, J., and Fibiger, H. C. 1992. Dopaminergic regulation of cortical acetylcholine release. Synapse 12:281–286.

    Google Scholar 

  18. Umbriaco, D., Watkins, K. C., Descarries, L., Cozzari, C., and Hartman, B. K. 1994. Ultrastructural and morphometric features of the acetylcholine innervation in adult rat parietal cortex: an electron microscopic study in serial sections. J. Comp. Neurol. 348:351–373.

    Google Scholar 

  19. Cuadra, G., Summers, K., and Giacobini E. 1994. Cholinesterase inhibitor effects on neurotransmitters in rat cortex in vivo. J. Pharmacol. Exp. Ther. 270(1):277–284.

    Google Scholar 

  20. Cuadra, G., and Giacobini E. 1995. Co-administration of cholinesterase inhibitors and idazoxan: effects of neurotransmitters in rat cortex in vivo. J. Pharmacol. Exptl. Ther. (In Press).

  21. Xu, M., Nakamura, Y., Yamamoto, T., Natori, K., Irie, T., Utsumi, H., and Kato T. 1991. Determination of basal acetylcholine release in vivo by rat brain dialysis with a U-shaped cannula: Effect of SM-10888, a putative therapeutic drug for Alzheimer's disease. Neurosci. Lett. 123:179–182.

    Google Scholar 

  22. Messamore, E., Warpman, U., Ogane, N., and Giacobini E. 1993b. Cholinesterase inhibitor effects on extracellular acetylcholine in rat cortex. Neuropharmacology 32:745–750.

    Google Scholar 

  23. DeBoer, P., Westerink, B. H. C., De Vries, J. B., and Horn, A. S. 1990. The effect of acetylcholinesterase inhibition on the release of acetylcholine from striatum in vivo: Interaction with autoreceptors responses. Neurosci. Lett. 116:357–360.

    Google Scholar 

  24. Kawashima, K., Hayakawa, T., Kashima, Y., Suzuki, T., Fujimoto, K., and Oohata, H. 1991. Determination of acetylcholine release in the striatum of anaesthetized rats using in vivo microdialysis and a radioimmunoassay. J. Neurochem. 57:882–887.

    Google Scholar 

  25. Messamore, E., Ogane, N., and Giacobini, E. 1993a. Cholinesterase inhibitor effects on extracellular acetylcholine in rat striatum. Neuropharmacology 32:291–296.

    Google Scholar 

  26. Johnson, C. D., and Russell, R. L. 1975. A rapid, simple radiometric assay for cholinesterase, suitable for multiple determinations. Anal. Biochem. 64:229–238.

    Google Scholar 

  27. Soininen, H., Unni, L., and Shillcutt, S. 1990. Effect of acute and chronic cholinesterase inhibition on biogenic amines in rat brain. Neurochem. Res. 15(12):1185–1190.

    Google Scholar 

  28. Unni, L. K., Womack, C., Hannant, M. E., and Becker, R. E. 1994. Pharmacokinetics and pharmacodynamics of metrifonate in humans. Meth. Find. Exp. Clin. Pharmacol. 16(4):285–289.

    Google Scholar 

  29. Becker, R. E., and Giacobini, E. 1988. Mechanisms of cholinesterase inhibition in senile dementia of the Alzheimer type: Clinical, pharmacological and therapeutic aspects. Drug Dev. Res. 12:163–195.

    Google Scholar 

  30. Summers, K., Cuadra, G., Naritoku, D., and Giacobini E. 1994. Effects of nicotine on levels of acetylcholine and biogenic amines in rat cortex. Drug Dev. Res. 31:108–119.

    Google Scholar 

  31. Knapp, M. J., Knopman, D. S., Solomon, P. R., Pendlebury, W. W., Davis, C. S., and Gracon, S. I. 1994. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. J. Amer. Med. Assoc. 271(13):985–991.

    Google Scholar 

  32. Thal, L. J., Masur, D. M., Fuld, P. A., Sharpless, N. S., and Davies, P. 1983. Memory improvement with oral physostigmine and lecithin in Alzheimer's disease. Pages 461–469,in Katzman, R. (ed.), Biological Aspects of Alzheimer Disease—Banbury Report 15, Cold Spring Harbor.

  33. Imbimbo, B. P., and Lucchelli, P. E. 1994. A pharmacodynamic strategy to optimize the clinical response to eptastigmine (MF-201). Pages 103–107,in Giacobini, E., and Becker, R. (eds), Alzheimer Disease—Therapeutic Strategies, Birkhauser Boston, Cambridge.

    Google Scholar 

  34. DeSarno, P., Pomponi, M., Giacobini, E., Tang, X. C., and Williams, E. 1989. The effect of heptylphysostigmine, a new cholinesterase inhibitor, on central cholinergic system in the rat. Neurochem. Res. 14:971–977.

    Google Scholar 

  35. Messamore, E., Warpman, U., Williams, E., and Giacobini, E. 1993c. Muscarinic receptors mediate attenuation of extracellular acetylcholine levels in rat cerebral cortex after cholinesterase inhibition. Neurosci. Lett. 158:205–208.

    Google Scholar 

  36. Reiner, E., Krauthacker, B., Simeon, B., and Skrinjaric-Spoljar, M. 1975. Mechanism of inhibition in vitro of mammalian acetylcholinesterase and cholinesterase in solution of 0,0-dimethyl 2,2,2-trichloro-1-hydroxyethyl phosphonate (Trichlorfon). Biochem. Pharmacol. 24:717–722.

    Google Scholar 

  37. Nordgren, I., Bergstrom, M., Holmstedt, B., and Sandoz, M. 1978. Transformation and action of metrifonate. Arch. Toxicol. 41:31–41.

    Google Scholar 

  38. Santucci, A. C., Haroutunian, V. and Davis, K. L. 1991. Pharmacological alleviation of combined cholinergic/noradrenergic lesion-induced memory deficits in rats. Clin. Neuropharmacol. 14: 1–8.

    Google Scholar 

  39. Moroni, F., Tanganelli, S., Antonelli, T., Carla, V., Bianchi, C., and Beani, L. 1983. Modulation of cortical acetylcholine and aminobutyric acid release in freely moving guinea pigs: Effects of clonidine and other adrenergic drugs. J. Pharmacol. Exp. Ther. 236:230–236.

    Google Scholar 

  40. Beani, L., Tanganelli, S., Antonelli, T., and Bianchi, C. 1986. Noradrenergic modulation of cortical acetylcholine release in both direct and gamma-aminobutyric acid-mediated. J. Pharmacol. Exp. Ther. 236:230–236.

    Google Scholar 

  41. Egan, T. M., and North, R. A. 1985. Acetylcholine acts on M2-muscarinic receptors to excite rat locus coeruleus neurons. Brit. J. Pharmacol. 85:733–735.

    Google Scholar 

  42. Wise, R. A. 1978. Catecholamine theories of reward: A critical review. Brain Res. 152:215–247.

    Google Scholar 

  43. Beninger, R. J. 1983. The role of dopamine in locomotor activity and learning. Brain Res. Rev. 6:173–196.

    Google Scholar 

  44. Baldwin, H. A., De Souza, R. J., Sarna, G. S., Murray, T. K., Green, A. R., and Cross, A. J. 1991. Measurements of tacrine and monoamines in brain by in vivo microdialysis argue against release of monoamines by tacrine at therapeutic doses. Brit. J. Pharmacol. 103:1946–1950.

    Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, Southern Illinois University School of Medicine, P.O. Box 19230, 62794-1222, Springfield, IL

    Francesca Mori, Gabriel Cuadra & Ezio Giacobini

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Mori, F., Cuadra, G. & Giacobini, E. Metrifonate effects on acetylcholine and biogenic amines in rat cortex. Neurochem Res 20, 1081–1088 (1995). https://doi.org/10.1007/BF00995563

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