, Volume 30, Issue 4, pp 329–342 | Cite as

Acute and chronic tolerance to nicotine measured by activity in rats

  • I. P. Stolerman
  • R. Fink
  • M. E. Jarvik
Animal Studies


Spontaneous locomotor activity has been used to assess the development and the dissipation of tolerance to nicotine in rats. Nicotine administered i.p. to experimentally naive rats depressed activity in a Y-shaped runway in a dose-related manner. After a single i.p. dose of nicotine, acute tolerance to the depressant action of a second dose developed with a definite time-course, becoming maximal after 2 h and wearing off after about 8 h. Repeated i.p. doses of nicotine (3 times daily for 8 days) elicited chronic tolerance, which was found to persist for at least 90 days after the end of regular treatment with the drug. Tolerance was also produced when nicotine was administered in rats' drinking water and through reservoirs implanted subcutaneously. We conclude that tolerance to nicotine in rats can develop quickly, may be measured easily, and persists for prolonged periods after withdrawal. A nicotine abstinence syndrome was not detected. The doses (mg/kg i.p.) of nicotine necessary to induce chronic tolerance in rats were similar to those probably obtained by cigarette smokers, but the different routes and rates of administration make precise comparisons difficult. However, it is suggested that relapse to tobacco use in man may be associated with the persistence of tolerance.


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  1. Armitage, A. K., Hall, G. H.: Nicotine, smoking and cortical activation. Nature (Lond.) 219, 1179–1180 (1968).Google Scholar
  2. Beckett, A. H., Triggs, E. J.: Determination of nicotine and its metabolite, cotinine, in urine by gas chromatography. Nature (Lond.) 211, 1415–1417 (1966).Google Scholar
  3. Beckett, A. H., Triggs, E. J.: Enzyme induction in man caused by smoking. Nature (Lond.) 216, 587 (1967).Google Scholar
  4. Bhattacharya, I. C., Goldstein, L.: Influence of acute and chronic nicotine administration on intra- and inter-structural relationships of the electrical activity in the rabbit brain. Neuropharmacol. 9, 109–118 (1970).Google Scholar
  5. Behrend, A., Thienes, C. H.: The development of tolerance to nicotine by rats. J. Pharmacol. exp. Ther. 48, 317–325 (1933).Google Scholar
  6. Bovet-Nitti, F.: Facilitation of simultaneous visual discrimination by nicotine in the rat. Psychopharmacologia (Berl.) 10, 59–66 (1966).Google Scholar
  7. Dixon, W. E., Lee, W. E.: Tolerance to nicotine. Quart. J. exp. Physiol. 5, 373–383 (1912).Google Scholar
  8. Domino, E. F.: Some behavioral actions of nicotine. In: Tobacco alkaloids and related compounds. U.S. von Euler (Ed.), pp. 145–162. Oxford: Pergamon 1965.Google Scholar
  9. Federal Trade Commission. Report of “Tar” and nicotine content of the smoke of 121 varieties of cigarettes. Washington, August 1971.Google Scholar
  10. Ginzel, K. H., Eldred, E., Watanabe, S., Grover, F.: Drug-induced depression of gamma efferent activity-1. Peripheral reflexogenic effect of nicotine. Neuropharmacol. 9, 151–167 (1970).Google Scholar
  11. Goldfarb, J.: Action of nicotine on reflexes in spinal cats. Neuropharmacol. 10, 399–412 (1971).Google Scholar
  12. Goldstein, A. Goldstein, D. B.: Enzyme expansion theory of drug tolerance and physical dependence. Res. Publ. Ass. nerv. ment. Dis. 46, 265–267 (1968).Google Scholar
  13. Goode, P. G.: An implanted reservoir of morphine solution for rapid induction of physical dependence in rats. Brit. J. Pharmacol. 41, 558–566 (1971).Google Scholar
  14. Hatcher, R. A.: Nicotine tolerance in rabbits, and the difference in the fatal dose in adult and young guinea pigs. Amer. J. Physiol. 11, 17–27 (1904).Google Scholar
  15. Jaffe, J. H., Sharpless, S. K.: Pharmacological denervation supersensitivity in the central nervous system: a theory of physical dependence. Res. Publ. Ass. nerv. ment. Dis. 46, 226–243 (1968).Google Scholar
  16. Jarvik, M. E.: The role of nicotine in the smoking habit. In: Learning mechanisms in smoking. W. A. Hunt (Ed.), pp. 155–190. Chicago: Aldine Pub. Co. 1970.Google Scholar
  17. Jarvik, M. E.: Further observations on nicotine as the reinforcing agent in smoking. In: Smoking Behavior: Motives and Incentives. W. L. Dunn (Ed.), pp. 33–49. Washington, D.C.: Winston 1973.Google Scholar
  18. Larson, P. S., Haag, H. B., Silvette, H.: Tobacco: experimental and clinical studies. Baltimore: Williams and Wilkins 1961.Google Scholar
  19. Larson, P. S., Silvette, H.: Tobacco: experimental and clinical studies. Supplement 1. Baltimore: Williams and Wilkins 1968.Google Scholar
  20. Martin, W. R.: A homeostatic and redundancy theory of tolerance to and dependence on narcotic analgesics. Res. Publ. Ass. nerv. ment. Dis. 46, 206–223 (1968).Google Scholar
  21. Morrison, C. F., Stephenson, J. A.: The occurrence of tolerance to a central depressant action of nicotine. Brit. J. Pharmacol. 46, 151–156 (1972).Google Scholar
  22. Morrison, C. F., Goodyear, J. M., Sellers, C. M.: Antagonism by antimuscarinic and ganglion-blocking drugs of some of the behavioural effects of nicotine. Psychopharmacologia (Berl.) 15, 341–350 (1969).Google Scholar
  23. Morrison, C. F., Lee, P. N.: A comparison of the effects of nicotine and physostigmine on a measure of activity in the rat. Psychopharmacologia (Berl.) 13, 210–221 (1968).Google Scholar
  24. Pradhan, S. N., Bowling, C.: Effects of nicotine on self-stimulation in rats. J. Pharmacol. exp. Ther. 176, 229–243 (1971).Google Scholar
  25. Report of the Advisory Committee to the Surgeon General of the Public Health Service: Smoking and Health. U.S. Public Health Service Publication 1103, Washington 1964.Google Scholar
  26. Rottenstein, H., Pierce, G., Russ, E., Felder, D., Montgomery, H.: Influence of nicotine on the blood flow of resting skeletal muscle and of the digits in normal subjects. Ann. N.Y. Acad. Sci. 90, 102–113 (1960).Google Scholar
  27. Rushton, R., Steinberg, H.: Mutual potentiation of amphetamine and amylobarbitone measured by activity in rats. Brit. J. Pharmacol. 21, 295–305 (1963).Google Scholar
  28. Rushton, R., Steinberg, H.: Drug combinations and their analysis by means of exploratory activity in rats. In: Neuropsychopharmacology. H. Brill et al. (Eds.), pp. 464–470. Amsterdam: Excerpta Medica 1967.Google Scholar
  29. Seevers, M. H.: Discussion. Res. Publ. Ass. nerv. ment. Dis. 46, 243–245 (1968).Google Scholar
  30. Seevers, M. H., Deneau, G. A.: Physiological aspects of tolerance and physical dependence, pp. 565–640. In: Physiological Pharmacology, vol. 1. W. S. Root and F. G. Hofmann (Eds.). New York: Academic Press 1963.Google Scholar
  31. Stitzer, M., Morrison, J., Domino, E. F.: Effects of nicotine on fixed-interval behavior and their modification by cholinergic antagonists. J. Pharmacol. exp. Ther. 171, 166–177 (1970).Google Scholar
  32. Wenzel, D. G., Azmeh, N.: Chronically administered nicotine and the blood pressure of normotensive and renal hypertensive rats. Arch. int. Pharmacodyn. 187, 367–376 (1970).Google Scholar
  33. Wenzel, D. G., Azmeh, N., Clark, I. J.: Studies on the acute and chronic depressor actions of nicotine in the rat. Arch. int. Pharmacodyn. 193, 23–36 (1971).Google Scholar
  34. Westfall, T. C.: Tobacco alkaloids and the release of catecholamines. In: Tobacco alkaloids and related compounds. U.S. von Euler (Ed.), pp. 179–201. Oxford: Pergamon 1965.Google Scholar
  35. Winer, B. J.: Statistical principles in experimental design. New York: McGraw-Hill 1962.Google Scholar

Copyright information

© Springer-Verlag 1973

Authors and Affiliations

  • I. P. Stolerman
    • 1
    • 2
  • R. Fink
    • 1
  • M. E. Jarvik
    • 1
  1. 1.Department of PharmacologyAlbert Einstein College of MedicineNew York
  2. 2.Department of PsychologyUniversity of CaliforniaLos AngelesUSA

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