, Volume 50, Issue 2, pp 107–112 | Cite as

Temporal relationship of the induction of tolerance and physical dependence after continuous intoxication with maximum tolerable doses of ethanol in rats

  • Edward Majchrowicz
  • Walter A. Hunt
Original Investigations


Rats were treated by intragastric intubation of a 20% ethanol solution in doses of 9–15 g/kg in 3–5 fractions for 1–7 days. Both tolerance and physical dependence were demonstrated after this treatment with the maximum tolerable doses to only a few days. Tolerance was assessed by signs of severity of intoxication: coma, loss of righting reflex, ataxia-3, ataxia-2, ataxia-1, sedation, and neutrality. During withdrawal, as blood ethanol concentrations approached 100 mg/dl the ethanol dependence phase was characterized by the onset of signs and responses of progressive severity: hyperactivity, tremors, spastic rigidity, and spontaneous convulsive seizures. A significant degree of tolerance was demonstrated for all signs of intoxication after 4 days of treatment, but did not reach maximum level even after 7 days. The severity of the withdrawal reactions intensified progressively to a maximum intensity after 4 days of treatment when as many as 72% of animals exhibited severe withdrawal signs and reactions including convulsive seizures. These different time courses suggest that tolerance and physical dependence are mediated through different mechanisms.

Key words

Tolerance to ethanol Physical dependence on ethanol Sustained intoxication with ethanol Ethanol withdrawal syndrome Model of physical dependence on ethanol Blood ethanol concentrations 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ahlenius, S., Engel, J.: Behavioral stimulation induced by ethanol withdrawal. Pharmacol. Behav. 2, 847–850 (1974)Google Scholar
  2. Allan, F. D., Swinyard, C. A.: Evaluation of tissue tolerance to ethyl alcohol by alterations in electroshock seizure thresholds in rats. Anat. Rec. 103, 419 (1949)Google Scholar
  3. Collier, H. O. J.: A general theory of the genesis of drug dependence by induction of receptors. Nature (Lond.) 205, 181–182 (1965)Google Scholar
  4. Ellis, F. W., Pick, J. R.: Experimentally induced ethanol dependence in rhesus monkeys. J. Pharmacol. exp. Ther. 175, 88–93 (1970)Google Scholar
  5. Essig, C. F., Lam, R. C.: Convulsions and hallucinatory behavior following alcohol withdrawal in the dog. Arch. Neurol. (Chic.) 18, 626–632 (1968)Google Scholar
  6. Freund, G.: Alcohol withdrawal syndrome in mice. Arch. Neurol. (Chic.) 21, 315–320 (1969)Google Scholar
  7. Freund, G.: Induction of physical dependence on alcohol in rodents. In: Biochemical pharmacology of ethanol, E. Majchrowicz, ed., Advanc. exp. Biol. Med., vol. 56, pp. 311–326. New York-London: Plenum Press 1975Google Scholar
  8. Freund, G., Walker, D. W.: Sound-induced seizures during ethanol withdrawal in mice. Psychopharmacologia (Berl.) 22, 45–59 (1971)Google Scholar
  9. Gibbins, R. J., Kalant, H., LeBlanc, A. E.: A technique for accurate measurement of moderate degrees of alcohol intoxiation in small animals. J. Pharmacol. exp. Ther. 159, 236–242 (1968)Google Scholar
  10. Gibbins, R. J., Kalant, H., LeBlanc, A. E., Clark, J. W.: The effects of chronic administration of ethanol on startle thresholds in rats. Psychopharmacologia (Berl.) 19, 95–104 (1971)Google Scholar
  11. Goldberg, L.: Quantitative studies of alcohol tolerance in man. Acta physiol. scand. 5, Suppl. 16, 1–128 (1943)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. Goldstein, D. B.: Relationship of alcohol dose to the intensity of withdrawal signs in mice. J. Pharmacol. exp. Ther. 180, 203–215 (1972)Google Scholar
  14. Goldstein, D. B.: Rates of onset and decay of alcohol physical dependence in mice. J. Pharmacol. exp. Ther. 190, 377–383 (1974)Google Scholar
  15. Goldstein, D. B., Pal, N.: Alcohol dependence produced in mice by inhalation of alcohol: grading the withdrawal reaction. Science 172, 288–290 (1971)Google Scholar
  16. Gross, M. M., Lewis, E., Hastey, J.: Acute alcohol withdrawal syndrome. In: The biology of alcoholism, B. Kissin and H. Begleiter, eds., Vol. 3, Clinical pathology, pp. 191–263. New York: Plenum Press 1973Google Scholar
  17. Hunt, W. A.: Changes in the neuroexcitability of alcohol-dependent rats undergoing withdrawal as measured by the pentalenetetrazole seizure threshold. Neuropharmacology 12, 1097–1102 (1973)Google Scholar
  18. Hunter, B. E., Boast, C. A., Walker, D. W., Zornetzer, S. F.: Alcohol withdrawal syndrome in rats: neural and behavioral correlates. Pharmacol. Biochem. Behav. 1, 719–725 (1973)Google Scholar
  19. Isbell, H., Fraser, H. F., Wikler, A., Belleville, R. E., Eisenmun, A. J.: An experimental study of the etiology of “rumfits” and delirium tremens. Quart. J. Stud. Alcohol. 16, 1–33 (1955)Google Scholar
  20. Jellinek, E. M.: The disease concept of alcoholism. Highland Park, N.J.: Hillhouse Press 1960Google Scholar
  21. Kalant, H., LeBlanc, A. F., Gibbins, R. J.: Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmacol. Rev. 23, 135–191 (1971)Google Scholar
  22. LeBlanc, A. F., Gibbins, R. J., Kalant, H.: Behavioral augmentation of tolerance to ethanol in the rats. Psychopharmacologia (Berl.) 30, 117–122 (1973)Google Scholar
  23. LeBlanc, A. F., Kalant, H., Gibbins, R. J.: Acute tolerance to ethanol in the rat. Psychopharmacologia (Berl.) 41, 43–46 (1975)Google Scholar
  24. LeBlanc, A. F., Kalant, H., Gibbins, R. J., Berman, N. D.: Acquisition and loss of tolerance to ethanol by the rat. J. Pharmacol. exp. Ther. 168, 244–250 (1969)Google Scholar
  25. Lester, D., Freed, E. X.: Criteria for an animal model of alcoholism. Pharmacol. Biochem. Behav. 1, 103–107 (1973)Google Scholar
  26. Majchrowicz, E.: Determination of ethanol, methanol and acetone in biological fluids by automated gas chromatography. Am. Chem. Soc. Div. Biol. Chem. 289, abs. (1971)Google Scholar
  27. Majchrowicz, E.: Induction of physical dependence on alcohol and the associated metabolic and behavioral changes in rats. Pharmacologist 15, 159, abs. (1973)Google Scholar
  28. Majchrowicz, E.: Spectrum and continuum of ethanol intoxication and withdrawal in rats. Pharmacologist 16, 304 (1974)Google Scholar
  29. Majchrowicz, E.: Induction of physical dependence upon ethanol and the associated behavioral changes in rats. Psychopharmacologia (Berl.) 43, 245–254 (1975)Google Scholar
  30. Majchrowicz, E., Bercaw, B. L., Cole, W. M., Gregory, D. H.: Nicotinamide adenine dinucleotide and the metabolism of ethanol and acetaldehyde. Quart. J. Stud. Alcohol 28, 213–224 (1967)Google Scholar
  31. Majchrowicz, E., Mendelson, J. H.: Blood methanol concentrations during experimentally induced ethanol intoxication in alcoholics. J. Pharmacol. exp. Ther. 179, 293–300 (1971)Google Scholar
  32. McQuarrie, D. G., Fingl, E.: Effects of single doses and chronic administration of ethanol on experimental seizures in mice. J. Pharmacol. exp. Ther. 124, 264–271 (1958)Google Scholar
  33. Mellanby, E.: Alcohol: its absorption into and disappearance from the blood under different conditions. Special Report Series No. 31, Medical Research Committee (1919)Google Scholar
  34. Mello, N. K.: A review of methods to induce alcohol addiction in animals. Pharmacol. Biochem. Behav. 1, 89–101 (1973)Google Scholar
  35. Mendelson, J. H. (ed.): Experimentally induced chronic intoxication and withdrawal in alcoholics. Quart. J. Stud. Alcohol, Suppl. No. 2 (1964)Google Scholar
  36. Mirsky, J. A., Piker, P., Rosenbaum, M., Ledever, N.: “Adaptation” of the central nervous system to varying concentrations of alcohol in the blood. Quart. J. Stud. Alcohol 2, 35–45 (1941)Google Scholar
  37. Newman, H. W., Lehman, A. J.: Nature of acquired tolerance to alcohol. J. Pharmacol. exp. Ther. 62, 301–306 (1938)Google Scholar
  38. Pieper, W. A.: Induction of physical dependence upon alcohol in nonhuman primates. In: Biochemical pharmacology of ethanol, E. Majchrowicz, ed., Advanc. exp. Biol. Med., vol. 56, pp. 327–337. New York-London: Plenum Press 1975Google Scholar
  39. Ratcliff, F.: Ethanol dependence in the rat: its production and characteristics. Arch. int. Pharmacodyn. 196, 146–156 (1972)Google Scholar
  40. Roach, M. K., Creaven, P. J.: A micromethod for the determination of acetaldehyde and ethanol in blood. Clin. chim. Acta 21, 275–278 (1968)Google Scholar
  41. Seevers, M. H., Deneau, G. A.: Physiological aspects of tolerance and physical dependence. In: Physiological pharmacology, Vol. 1, W. S. Root and E. G. Hofmann, eds., pp. 565–640. London: Academic Press 1963Google Scholar
  42. Victor, M.: Treatment of alcoholic intoxication and the withdrawal syndrome. A critical analysis of the use of drugs and other forms of therapy. Psychosom. Med. 33, 636–650 (1966)Google Scholar
  43. Victor, M., Adams, R. D.: The effect of alcohol on the nervous system. Res. Publ. Ass. nerv. ment. Dis. 32, 526–573 (1953)Google Scholar
  44. Wallgren, H., Lindbohm, R.: Adaptation to ethanol in rats with special reference to brain tissue respiration. Biochem. Pharmacol. 8, 423–424 (1961)Google Scholar
  45. Way, E. L., Loh, H. H., Shen, R.-H.: Simultaneous quantitative assessment of morphine tolerance and physical dependence. J. Pharmacol. exp. Ther. 167, 1–8 (1969)Google Scholar

Copyright information

© Springer-Verlag 1976

Authors and Affiliations

  • Edward Majchrowicz
    • 1
  • Walter A. Hunt
    • 2
  1. 1.L.A.R.National Institute on Alcohol Abuse and AlcoholismWashington, D.C.USA
  2. 2.Neurobiology DepartmentArmed Forces Radiobiology Research InstituteBethesdaUSA

Personalised recommendations