Biology of Tolerance and Dependence

  • Boris Tabakoff
  • Jeffrey D. Rothstein


Alcoholism is a heterogeneous phenomenon that involves maladaptive behavior, medical complications, and cultural attitudes, but all realistic definitions of alcoholism include reference to an individual’s tolerance to and dependence on ethanol (see Chapter 1). Alcohol tolerance and dependence, however, are not unidimen-sional entities; therefore it will be the purpose of this chapter to introduce the reader to the various facets of tolerance and dependence on ethanol, to discuss the implications of tolerance and dependence in promoting aberrant drinking behavior and alcohol-induced pathologies, and to describe the current treatment approaches used to manage the acute alcohol withdrawal syndrome.


Withdrawal Syndrome Alcohol Withdrawal Physical Dependence Ethanol Tolerance Ethanol Administration 
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  1. Adams, R. D. Coma and related disturbances of consciousness. In K. J. Isselbacher, R. J. Adams, E. Braunwald, R. G. Petersdorf, & J. D. Wilson (Eds.), Harrison’s principles of internal medicine (9th ed.). New York: McGraw-Hill, 1980.Google Scholar
  2. American Medical Association. American Medical Association drug evaluations (4th ed.). Chicago: American Medical Association, 1980.Google Scholar
  3. Antelman, S. M. & Caggiola, A. R. Norepinephrine-dopamine interactions and behavior. Science, 1977, 195, 646–653.CrossRefGoogle Scholar
  4. Belknap, J. R., Berg, J. H., & Coleman, R. R. Alcohol withdrawal and magnesium deficiency in mice. Pharmacology, Biochemistry and Behavior, 1978, 9(1), 1–6.CrossRefGoogle Scholar
  5. Blum, R., Eubanks, J. D., Wallace, J. E., & Hamilton, H. Enhancement of alcohol withdrawal convulsions in mice by haloperidol. Clinical Toxicology, 1976, 9, 427–434.CrossRefGoogle Scholar
  6. Borg, S., Kvande, H., & Sedvall, G. Central norepinephrine metabolism during alcohol intoxication in addicts and healthy volunteers. Science, 1981, 213, 1135–1137.CrossRefGoogle Scholar
  7. Carlen, P. L., Lee, M. A., Jacob, M., & Livshits, O. Parkinsonism provoked by alcoholism. Annals of Neurology, 1981, 9, 84–86.CrossRefGoogle Scholar
  8. Chutkow, J. G. Clinical-chemical correlations in encephalopathy of magnesium deficiency: Effect of reversal of magnesium deficits. Mayo Clinic Proceedings, 1974, 49, 244–247. (a)Google Scholar
  9. Chutkow, J. G. Metabolism of magnesium in central nervous system: Relationship between concentrations of magnesium in cerebrospinal fluid and brain in magnesium deficiency. Neurology (Minn.), 1974, 24, 780–787. (b)Google Scholar
  10. Collier, H. O. J. Supersensitivity and dependence. Nature, 1968, 220, 228–231.CrossRefGoogle Scholar
  11. Curran, M., & Seeman, P. Alcohol tolerance in a cholinergic nerve terminal: Relation to the membrane expansion-fluidization theory of ethanol action. Science, 1977, 197, 910.CrossRefGoogle Scholar
  12. DeWied, D., Bohus, B., van Wimersma Griedanus, Tj. B., & Gispen, W. H. Pituitary peptides and memory. In R. Walter & J. Meienhofer (Eds.), Peptides, chemistry, structure, biology. Ann Arbor, Mich.: Ann Arbor Scientific Publications, 1975.Google Scholar
  13. Frankel, D., Khanna, J. M., LeBlanc, A. E., & Kalant, H. Effect of p-chlorophenylalanine on the acquisition of tolerance to ethanol and pentobarbital. Psychopharmacology, 1975, 44, 247–252.CrossRefGoogle Scholar
  14. Frankel, D., Khanna, J. M., Kalant, H., & LeBlanc, A. E. Effect of p-chlorophenylalanine on the acquisition of tolerance to the hypothermic effects of ethanol. Psychopharmacology, 1979, 57, 239–242.CrossRefGoogle Scholar
  15. Gessner, P. R. Drug therapy of the alcohol withdrawal syndrome. In E. Majchrowicz & E. P. Noble (Eds.), Biochemistry and pharmacology of ethanol (Vol. 2). New York: Plenum Press, 1979.Google Scholar
  16. Golbert, T. M., Sanz, C. J., Rose, H. D., & Leitschuh, T. H. Comparative evaluation of treatments of alcohol withdrawal syndromes. Journal of the American Medical Association, 1967, 201, 99–102.CrossRefGoogle Scholar
  17. Goldstein, D. B. Alcohol withdrawal reactions in mice: Effects of drugs that modify neurotransmission. Journal of Pharmacology and Experimental Therapeutics, 1973, 186, 1–9.Google Scholar
  18. Goldstein, D. B., & Chin, J. H. Interaction of ethanol with biological membranes. Federation Proceedings, 1981, 40, 2073–2076.Google Scholar
  19. Goldstein, A., & Goldstein, D. B. Enzyme expansion theory of drug tolerance and physical dependence. In A. Wikler (Ed.), The addictive states. Baltimore: Williams & Wilkins, 1968.Google Scholar
  20. Goodman, L. S., & Gilman, A. (Eds.). The pharmacological basis of therapeutics (6th ed.). New York: Macmillan, 1980.Google Scholar
  21. Greenberg, R., & Pearlman, C. Delirium tremens and dreaming. American Journal of Psychiatry, 1967, 124, 133–142.Google Scholar
  22. Gross, M. M., Rosenblatt, S. M., Chartoff, S., Hermann, A., Schachter, M., Sheinkin, D., & Broman, M. Evaluation of acute alcohol psychoses and related states. The daily clinical course rating scale. Quarterly Journal of Studies of Alcohol, 32, 1971, 611–619.Google Scholar
  23. Gross, M. M., Rosenblatt, S. M., Lewis, E., Chartoff, S., & Malenowski, B. Acute alcoholic psychoses and related syndromes—Psychosocial and clinical characteristics and their implications. British Journal of Addiction, 1972, 67, 15–31.CrossRefGoogle Scholar
  24. Gross, M. M., Goodenough, D. R., Hastey, J., & Lewis, E. Experimental study of sleep in chronic alcoholics before, during and after four days of heavy drinking, with a nondrinking comparison. Annual New York Academy of Science, 1973, 215, 254–265.CrossRefGoogle Scholar
  25. Gross, M. M., Lewis, E., & Hastey, J. Acute alcohol withdrawal syndrome. In B. Kissin & H. Begleiter (Eds.), The biology of alcoholism (Vol. 3), Clinical pathology. New York: Plenum Press, 1974.Google Scholar
  26. Himmelsbach, C. R. Clinical studies of drug addiction. Archives of Internal Medicine, 69, 1942, 766–772.CrossRefGoogle Scholar
  27. Hoffman, P. L., Ritzmann, R. F., & Tabakoff, B. The influence of arginine vasopressin and oxytocin on ethanol dependence and tolerance. In M. Galanter (Ed.), Currents in alcoholism (Vol. 5). New York: Grune & Stratton, 1979.Google Scholar
  28. Hoffman, P. L., Ritzmann, R. F., Walter, R., & Tabakoff, B. Arginine vasopressin maintains ethanol tolerance. Nature (London), 1978, 276, 614–616.CrossRefGoogle Scholar
  29. Isbell, H. Alcohol proteins and alcoholism. In R. B. Beeson & W. McDermott (Eds.), Loeb’s textbook of medicine (12th ed.). Philadelphia: Saunders, 1967.Google Scholar
  30. Isbell, H., Fraser, H. F., Wikler, A., Belleville, R. E., & Eisenman, A. J. An experimental study of the etiology of “rum fits” and delirium tremens. Quarterly Journal of Studies of Alcohol, 1955, 16, 1–33.Google Scholar
  31. Jaffe, J. H., & Sharpless, S. K. Pharmacological denervation supersensitivity in the central nervous system: A theory of physical dependence. In A. Wikler (Ed.), The addictive states. Baltimore: Williams & Wilkins, 1968.Google Scholar
  32. Johnson, L. C., Burdick, A., & Smith, J. Sleep during alcohol intake and withdrawal in the chronic alcoholic. Archives of General Psychology, 1970, 22, 406–418.CrossRefGoogle Scholar
  33. Kalant, H., LeBlanc, A. E., & Gibbins, R. J. Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmacology Review, 1971, 23, 135–191.Google Scholar
  34. Kalant, H., LeBlanc, A. E., & Gibbins, R. J. Repetitive development of ethanol tolerance. Psychopharmacology, 1978, 60, 59–65. (a)CrossRefGoogle Scholar
  35. Kalant, H., LeBlanc, A. E., Gibbins, R. J., & Wilson, A. Accelerated development of tolerance during repeated cycles of ethanol exposure. Psychopharmacology, 1978, 60, 59–65. (b)CrossRefGoogle Scholar
  36. Kissin, B., & Gross, M. M. Drug therapy in alcoholism. American Journal of Psychiatry, 1968, 125, 31–41.Google Scholar
  37. LeBlanc, A. E., & Cappell, H. Tolerance as adaptation: Interactions with behavior and parallels to other adaptive processes. In K. Blum (Ed.), Alcohol and opiates: Neurochemical and behavior mechanisms. New York: Academic Press, 1977.Google Scholar
  38. LeBlanc, A. E., Kalant, H., Gibbins, R. J., & Berman, N. D. Acquisition and loss of tolerance to ethanol by the rat. Journal of Pharmacology and Experimental Therapeutics, 1969, 168, 244–250.Google Scholar
  39. LeBlanc, A. E., Gibbins, R. J., & Kalant, H. Generalization of behaviorally augmented tolerance to ethanol and its relation to physical dependence. Psychopharmacology, 1975, 44, 241–246.CrossRefGoogle Scholar
  40. Lester, B. K., Rundell, O. H., Cowden, L. C., & Williams, H. L. Chronic alcoholism, alcohol and sleep. In M. M. Gross (Ed.), Alcohol intoxication and withdrawal: Experimental studies (Vol. 1). New York: Plenum Press, 1973.Google Scholar
  41. Martin, W. R. Pharmacological redundancy as an adaptive mechanism in the CNS. Federation Proceedings, 1970, 29, 13–18.Google Scholar
  42. Masur, J., & Boerngen, R. The excitatory component of ethanol in mice: A chronic study. Pharmacology, Biochemistry and Behavior, 1980, 13, 777–780.CrossRefGoogle Scholar
  43. Melchior, C. L., & Tabakoff, B. Modification of environmentally cued tolerance to ethanol in mice. Journal of Pharmacology and Experimental Therapeutics, 1981, 219, 175–180.Google Scholar
  44. Mellanby, E. Alcohol: Its absorption into and disappearance from the blood under different conditions. Medical Research Council, Special Report Series (London), 1919, 15, 1–48.Google Scholar
  45. Mello, N. K. Behavioral studies of alcoholism. In B. Kissin & H. Begleiter (Eds.), The biology of alcoholism (Vol. 2). New York: Plenum Press, 1972.Google Scholar
  46. Mellor, C. S., & Ganguli, R. Semiography of tremor in alcohol withdrawal. In M. Galanter (Ed.), Currents in alcoholism (Vol. 5). New York: Grune & Stratton, 1979.Google Scholar
  47. Mendelson, J. H., & LaDou, J. Experimentally induced chronic intoxication and withdrawal in alcoholics. Part 2—Psychophysiological findings. Quarterly Journal on Studies of Alcohol, 1964, Suppl. 2, 14–39.Google Scholar
  48. Renaud, B., Buda, M., Lewis, B. P., & Pujol, J. K. Effects of 5,6-dihydroxytryptamine on tyrosine-hydroxylase activity in central catecholaminergic neurons of the rat. Biochemical Pharmacology, 1975, 24, 1739–1742.CrossRefGoogle Scholar
  49. Ritzmann, R. F., & Tabakoff, B. Body temperature in mice: A quantitative measure of alcohol tolerance and physical dependence. Journal of Pharmacology and Experimental Therapeutics, 1976, 199, 158–170.Google Scholar
  50. Roffman, M., & Lal, H. Stimulus control of hexobarbital narcosis and metabolism in mice. Journal of Pharmacology and Experimental Therapeutics, 1974, 191, 358–369.Google Scholar
  51. Searle, G. L., Shames, D., Cavalier, R. R., Bagdade, J. D., & Porte, D., Jr. Evaluation of ethanol hypoglycemia in man: Turnover studies with C-6-14C glucose. Metabolism, 1974, 23, 1023–1035.CrossRefGoogle Scholar
  52. Seeman, P. The membrane actions of anesthetics and tranquilizers. Pharmacology Review, 1972, 24, 583–655.Google Scholar
  53. Sellers, E. M., & Kalant, H. Drug therapy: Alcohol intoxication and withdrawal. New England Journal of Medicine, 1976, 294, 757–762.CrossRefGoogle Scholar
  54. Sellers, E. M., Zilm, D. H., & Degani, N. C. Comparative efficacy of propranolol and chlordiazepoxide in alcohol withdrawal. Journal of Studies in Alcohol, 1977, 38, 2096–2108.Google Scholar
  55. Siegel, S. Evidence from rats that morphine tolerance is a learned response. Journal of Comparative and Physiological Psychology, 1975, 89, 498–506.CrossRefGoogle Scholar
  56. Spealman, R. D., & Goldberg, S. R. Drug self-administration by laboratory animals: Control by chedules of reinforcement. Annual Review of Pharmacological Toxicology, 1978, 18, 313–339.CrossRefGoogle Scholar
  57. Tabakoff, B. Alcohol tolerance in humans and animals. In K. Eriksson, J. D. Sinclair, & K. Kiianmaa (Eds.), Animal models in alcohol research. New York: Academic Press, 1980.Google Scholar
  58. Tabakoff, B., & Hoffman, P. L. Alcohol and neurotransmitters. In H. Rigter & J. C. Crabbe (Eds.), Alcohol tolerance and dependence. Amsterdam: Elsevier/North Holland, 1980.Google Scholar
  59. Tabakoff, B., & Hoffman, P. L. Neurochemical aspects of tolerance and physical dependence on alcohol. In B. Kissin & H. Begleiter (Eds.), The biology of alcoholism (Vol. 7). New York: Plenum Press, 1983.Google Scholar
  60. Tabakoff, B., & Ritzmann, R. F. The effects of 6-hydroxydopamine on tolerance to and dependence on ethanol. Journal of Pharmacology and Experimental Therapeutics, 1977, 203, 319–331.Google Scholar
  61. Thomas, D. W., & Freedman, D. X. Treatment of alcohol withdrawal syndrome: Comparison of promazine and paraldehyde. Journal of the American Medical Association, 1964, 188, 316–318.CrossRefGoogle Scholar
  62. Traynor, A. E., Schlapfer, W. T., & Barondes, S. H. Stimulation is necessary for the development of tolerance to a neuronal effect of ethanol. Journal of Neurobiology, 1980, 11, 633–637.CrossRefGoogle Scholar
  63. Victor, M. Treatment of alcoholic intoxication and the withdrawal syndrome. Psychosomatic Medicine, 1966, 28, 636–650.Google Scholar
  64. Victor, M., & Adams, R. D. The effect of alcohol in the nervous system. Research Publication, Association Research on Nervous and Mental Disorders, 1953, 32, 526–573.Google Scholar
  65. Victor, M., & Wolfe, S. M. Causation and treatment of the alcohol withdrawal syndrome. In P. B. Bourne & R. Fox (Eds.), Alcoholism progress in research and treatment. New York: Academic Press, 1973.Google Scholar
  66. Vogel, G. W. REM deprivation. III. Dreaming and psychosis. Archives of General Psychiatry, 1968, 18, 312–329.CrossRefGoogle Scholar
  67. Vogel-Sprott, M. Acute and chronic tolerance to low doses of alcohol: Differences in cognitive and motor skill performance. Pscychopharmacology, 1979, 61, 287–291.CrossRefGoogle Scholar
  68. Wahlstrom, G., & Ekwall, T. Tolerance to hexobarbital and supersensitivity to pilocarpine after chronic barbital treatments in the rat. European Journal of Pharmacology, 1976, 38, 123–129.CrossRefGoogle Scholar
  69. Walter, R., Hoffman, P. L., Flexner, J. B., & Flexner, L. B. Neurohypophyseal hormones, analogs and fragments: Their effects on puromycin-induced amnesia. Proceedings of the National Academy of Science, USA, 1975, 72, 4180–4184.CrossRefGoogle Scholar
  70. Wenger, J. R., Tiffany, T. M., Bombardier, C., Nicholls, K., & Woods, S. C. Ethanol tolerance in the rat is learned. Science, 1981, 213, 575–577.CrossRefGoogle Scholar
  71. Wolfe, V. M., & Victor, M. The physiological basis of the alcohol withdrawal syndrome. In N. K. Mello & J. H. Mendelson (Eds.), Recent advances in studies of alcoholism: An interdisciplinary symposium. Washington, D.C.: U.S. Government Printing Office, Pub. No. (HSM) 71–9045, 1971.Google Scholar
  72. Yuki, T., Bradford, B. V., & Thurman, R. G. Role of hormones in the mechanism of the swift increase in alcohol metabolism in the rat. Pharmacology, Biochemistry and Behavior, 13 (Suppl. 1), 1980, 67–71.CrossRefGoogle Scholar
  73. Zarcone, V. P., Schreier, L., Mitchell, G., Orenberg, E., & Barchas, J. Sleep variables, cyclic AMP and biogenic amine metabolites after one day of ethanol ingestion. Journal of Studies on Alcoholism, 1980, 41, 318–324.Google Scholar

Copyright information

© Plenum Press, New York 1983

Authors and Affiliations

  • Boris Tabakoff
    • 1
    • 2
  • Jeffrey D. Rothstein
    • 3
  1. 1.Westside Veterans Administration Medical CenterChicagoUSA
  2. 2.Alcohol and Drug Abuse Research and Training Program, Department of Physiology and BiophysicsUniversity of Illinois at the Medical CenterChicagoUSA
  3. 3.Department of Physiology and BiophysicsUniversity of Illinois at the Medical CenterChicagoUSA

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