, Volume 55, Issue 1, pp 43–48 | Cite as

On the interaction of drugs with the cholinergic nervous system

VI. Tolerance to physostigmine in mice
  • Saul Maayani
  • Yaakov Egozi
  • Irit Pinchasi
  • Mordechai Sokolovsky
Original Investigations


Tolerance to physostigmine salicylate was induced in mice using various schedules of s.c. injections. The rate and degree of tolerance development were assessed by comparing the ED50 values (equipotent doses) and by comparing the peak effects induced by a constant dose. These were measured on four systemic responses induced by the drug — hypothermia, tremor, salivation, and the effects measured in the rotarod test. The degree of tolerance development was found to be dose-dependent with a maximal achievable tolerance for every dose. The tolerance development to the four systemic effects differed in time course: tolerance to the hypothermia was induced even with daily injections, while tolerance to the salivation and rotarod effects could be detected only when the drug was given every 4 h. No tolerance developed to the tremor with any of the schedules and doses used. The maximal achievable tolerance degree and the pattern of changes of the duration were different for each systemic effect. The tolerance was found to be reversible, with different rates of recovery, for the different effects. The tolerance state could not be correlated with changes in the pattern of brain acetylcholinesterase (AcChE) inhibition by physostigmine in vivo or with changes in the rate of the enzyme's spontaneous reactivation.

Scopolamine. HBr given 10 min before physostigmine prevented tolerance development. In addition, cross-tolerance to various muscarinic agonists and cholinesterase inhibitors was found in the physostigmine-tolerant mice. The correlation between these results and our previous findings concerning possible biochemical adaptations is presented and discussed.

Key words

Tolerance Physostigmine Cholinergic nervous system Acetylcholinesterase 


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  1. Aston, R.: Acute tolerance indices to pentobarbital in male and female rats. J. Pharmacol. Exp. Ther. 152, 350–353 (1966)Google Scholar
  2. Bernards, W.: Case history number 74: reversal of phenothiazine coma with physostigmine. Anesth. Analg. 52, 938–941 (1973)Google Scholar
  3. Breznoff, H. E., Myćek, M. Y.: Central cholinergic involvement in barbiturates tolerance. Fed. Proc. 34, 779 (1974)Google Scholar
  4. Brimblecombe, W. R.: Drug actions on cholinergic system. In: Pharmacology monographs, P. B. Bradely, ed., pp. 63–132. Baltimore: University Park Press 1974Google Scholar
  5. Buckley, G. A., Heading, C. E.: Tolerance to neostigmine. Br. J. Pharmacol. 40, 590p-591p (1970)Google Scholar
  6. Carrol, B. J., Frazer, A., Schless, A., Mendels, J.: Cholinergic reversal of manic symptoms. Lancet 1973I, 427–428Google Scholar
  7. Chang, C. C., Chen, T. F., Chuang, S. T.: Influence of chronic neostigmine treatment on the number of acetylcholine receptors and the release of acetylcholine from the rat diaphragm. J. Physiol. 230, 613–618 (1973a)Google Scholar
  8. Chang, C. C., Chen, T. F., Chuang, S. T.: N, O-Di and N,N,O-tri-(3H) acetyl α-bungarotoxins as specific labeling agents of cholinergic receptors. Br. J. Pharmacol 47, 147–160 (1973b)Google Scholar
  9. Cheney, D. L., Goldstein, A., Sheehan, P.: Rate of development and reversibility of brain tolerance and physical dependence in mice treated with opiates. Fed. Proc. 29, 685 [abstract] (1970)Google Scholar
  10. Chiel, H., Yehuda, S., Wurtman, R. J.: Development of tolerance in rats to the hypothermic effect of d-amphetamine. Life Sci. 14, 483–488 (1974)Google Scholar
  11. Duvoisin, R. C., Katz, R.: Reversal of central anticholinergic syndrom in man by physostigmine. J. Am. Med. Assoc. 206, 1963–1965 (1968)Google Scholar
  12. Eddy, N. B., Pillar, M., Pirk, L. A., Schrappe, O., Wende, S.: The effect of addition of a narcotic antagonist on the rate and development of tolerance and physical dependence to morphine. Bull. Narc 12, 1–7 (1960)Google Scholar
  13. Ellman, G. L., Courtney, K. D., Andres, V., Jr., Featherstone, R. W.: A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 7, 88–95 (1961)Google Scholar
  14. El-Yousef, M. K., Janowsky, D. S., Davis, J. M., Sekerke, H. G.: Reversal of antiparkinson drug toxicity by physostigmine: a controlled study. Am. J. Psychiatry 130, 141–145 (1973)Google Scholar
  15. Falletta, J. M., Stasney, C. R., Mintz, A. A.: Amitriptylin poisoning treated with physostigmine. South Med. J. 63, 1492–1493 (1970)Google Scholar
  16. Freedman, D. X., Aghajanian, G. K., Ornitz, E. M., Rosner, B. S.: Patterns of tolerance to LSD and Mescaline in rats. Science 127, 1173–1174 (1958)Google Scholar
  17. Goldstein, A., Sheehan, P.: Tolerance to opioid narcotics. I. Tolerance to the “running fit” caused by levorphanol in mice. J. Pharmacol. Exp. Ther. 169, 175–184 (1969)Google Scholar
  18. Goldstein, A., Judson, B. A., Sheehan, P.: Cellular and metabolic tolerance to an opioid narcotic in mouse brain. Br. J. Pharmacol. 47, 138–140 (1973)Google Scholar
  19. Grancher, R. P., Baldessarini, R. J.: Physostigmine. Arch. Gen. Psychiatry 32, 375–380 (1975)Google Scholar
  20. Heiser, J. F., Wilbert, D. E.: Reversal of delirium induced by tricyclic antidepressant drugs with physostigmine. Am. J. Psychiatry 131, 1275–1277 (1974)Google Scholar
  21. Hug, C. C.: Characteristics and theories related to acute and chronic tolerance development. In: Chemical and biological aspects of drug dependence, S. J. Mulé and H. Brill, eds., pp. 307–358. Cleveland: CRS Press 1972Google Scholar
  22. Jaffe, J. H., Sharpless, S. K.: Pharmacological denervation supersensitivity in the central nervous system: a theory of physical dependence. In: The Addictive States, vol. 46, A. Wikler, ed., pp. 226–243. Baltimore William and Wilkins 1968Google Scholar
  23. Janowsky, D. S., El-Yousef, M. K., Davis, J. M., Sekerke, H. J.: A cholinergic-adrenergic hypothesis of mania and depression. Lancet 1972aII, 632–635Google Scholar
  24. Janowsky, D. S., El-Yousef, M. K., Davis, J. M., Hubbard, B., Sekerke, H. J.: Cholinergic reversal of manic symptoms. Lancet 1972bI, 1236–1237Google Scholar
  25. Janowsky, D. S., El-Yousef, M. K., Davis, J. M., Sekerke, H. G.: Parasympathetic suppression of manic symptoms by physostigmine. Arch. Gen. Psychiatry 28, 542–547 (1973)Google Scholar
  26. Kalant, H., Leblanc, A. E., Gibbins, R. J.: Tolerance to and dependence on some non-opiate psychotic drugs. Pharmacol. Rev. 23, 135–191 (1971)Google Scholar
  27. Ketchum, J. S., Sidell, F. R., Crowell, E. B., Jr., Aghajanian, G. K., Hayes, A. H., Jr.: Atropine, scopolamine and ditran: comparative pharmacology and antagonists in man. Psychopharmacologia (Berl.) 28, 121–145 (1973)Google Scholar
  28. Klee, W. A., Streaty, R. A.: Narcotic receptor in morphine-dependent rats. Nature 248, 61–63 (1974)Google Scholar
  29. Little, H. J., Rees, J. M. H.: Tolerance development to the antinociceptive actions of morphine, amphetamine, physostigmine and 2-aminoindane in the mouse. Experientia 30, 930–932 (1974)Google Scholar
  30. Maayani, S., Egozi, Y., Pinchasi, I., Sokolovsky, M.: On the interaction of drugs with the cholinergic nervous system. IV. Tolerance to oxotremorine in mice: in vivo and in vitro studies. Biochem. Pharmacol. 26, 1681–1687 (1977a)Google Scholar
  31. Maayani, S., Egozi, Y., Pinchasi, I., Sokolovsky, M.: On the interaction of drugs with the cholinergic nervous system. V. Characterization of some effects induced by physostigmine in mice: in vivo and in vitro studies. Biochem. Pharmacol. (in press, 1977b)Google Scholar
  32. Miledi, R., Potter, L. T.: Acetylcholine receptors in muscle fibers. Nature 233, 599–603 (1971)Google Scholar
  33. Mushlin, B. E., Grell, C. F., Cochin, J.: Studies on tolerance. 1. The role of interval between doses on the development of tolerance to morphine. J. Pharmacol. Exp. Ther. 196, 280–287 (1976)Google Scholar
  34. Newton, R.: Ami-triptylin and imipramine poisoning in children. Br. Med. J. 1974II, 176–177Google Scholar
  35. Orahovats, P. D., Winter, C. A., Lehman, E. G.: The effect of n-allynomophine upon the rate of tolerance development to morphine in the albino rat. J. Pharmacol. Exp. Ther. 109, 413–416 (1953)Google Scholar
  36. Pinchasi, I., Maayani, S., Sokolovsky, M.: On the interaction of drugs with the cholinergic nervous system. I. Tolerance to phenyclidine derivatives in mice: pharmacological characterization. Psychopharmacology (in press, 1977a)Google Scholar
  37. Pinchasi, I., Maayani, S., Egozi, Y., Sokolovsky, M.: On the interaction of drugs with the cholinergic nervous system. II. Cross-tolerance between phencyclidine derivatives and cholinergic drugs. Psychopharmacology (in press, 1977b)Google Scholar
  38. Pinchasi, I., Maayani, S., Sokolovsky, M.: On the interaction of drugs with the cholinergic nervous system. III. Tolerance to phencyclidine derivatives: in vivo and in vitro studies. Biochem. Pharmacol. 26, 1671–1679 (1977c)Google Scholar
  39. Rehavi, M., Maayani, S., Sokolovsky, M.: Tricyclic antidepressants as antimuscarinic drugs: in vivo and in vitro studies. Biochem. Pharmacol. 26, 1559–1567 (1977)Google Scholar
  40. Simpson, L. L.: The effects of lithium and physostigmine on rat brain acetylcholinesterase activity. Psychopharmacologia (Berl.) 38, 145–150 (1974)Google Scholar
  41. Slovis, T. L., Ott, J. E., Teitelbaum, D. T., Lipscomb, D.: Physostigmine therapy in acute tricyclic antidepressants poisoning. Clin. Toxicol. 4, 451–459 (1971)Google Scholar
  42. Smith, A. A., Karmin, M., Gavitt, J.: Tolerance to the lenticular effects of opiates. J. Pharmacol. Exp. Ther. 156, 85–91 (1967)Google Scholar
  43. Smith, A. A.: Inhibition of tolerance development. In: Narcotic drugs, biochemical pharmacology, D. H. Clouet, ed., pp. 424–432 New York: Plenum Press 1971Google Scholar
  44. Snyder, B. D., Blond, L., McWhirter, W. R.: Reversal of amitryptilline intoxication by physostigmine. J. Am. Med. Assoc. 230, 1433–1434 (1974)Google Scholar
  45. Stolerman, I. P., Bunker, P., Jarvik, M. E.: Nicotine tolerance in rats: role of dose and dose interval. Psychopharmacologia (Berl.) 34, 317–324 (1974)Google Scholar
  46. Vasquez, B. J., Overstreet, D. H., Russel, R. W.: Psychopharmacological evidence for increase in receptor sensitivity following chronic morphine treatment. Psychopharmacologia (Berl.) 38, 287–302 (1974)Google Scholar

Copyright information

© Springer-Verlag 1977

Authors and Affiliations

  • Saul Maayani
    • 1
  • Yaakov Egozi
    • 1
  • Irit Pinchasi
    • 1
  • Mordechai Sokolovsky
    • 1
  1. 1.Department of Biochemistry, The George S. Wise Center for Life SciencesTel-Aviv UniversityTel-AvivIsrael

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