Comparative Aspects of Tolerance to, and Dependence on, Alcohol, Barbiturates and Opiates

  • H. Kalant
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 85B)


Despite the known differences in mechanism of action of opiates and of the general depressants at molecular level, the withdrawal reactions after prolonged treatment with morphine, alcohol and barbiturates have many features in common. The main differences relate to the more prominent autonomic overactivity in opiate withdrawal, and the more prominent central overactivity (seizures, hallucinations, delirium) in alcohol and barbiturate withdrawal. Most of the neurochemical and neurophysiological phenomena so far examined are common to all three withdrawal reactions and are probably secondary to neuronal hyperactivity, rather than basic mechanisms of physical dependence.

The time course of development of tolerance is similar with all three drugs, as is the influence of dose, intensity of exposure, and behavioral demands on the organism during the period of drug action. Daily treatment with morphine in doses ranging from 7.5 to 45 mg/kg resulted in a tolerance curve with two apparently exponential components, an early steeper one and a later, less steep one. The slopes of both components increased with the dose. The suggestion of two components is also supported by differing patterns of within-session tolerance in rats exposed to ethanol before vs. after test sessions.

Administration of p-CPA significantly reduced the net rate of development of tolerance to ethanol and to pentobarbital, just as had earlier been shown for morphine. A hypothesis is offered to explain how drugs with very different molecular mechanisms of action can produce adaptive changes with many important features in common.


Physical Dependence Morphine Tolerance Alcohol Withdrawal Syndrome Opiate Withdrawal Tolerance Development 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adams, W. J., Yeh, S. Y., Woods, L. A., and Mitchell, C. L. Drug-test interaction as a factor in the development of tolerance to the analgesic effect of morphine. J. Pharmacol. Exp. Therap., 168:251–257, 1969.Google Scholar
  2. Adler, M. W., Lin, C., Smith, K. P., Tresky, R., and Gildenberg, P. L. Lowered seizure threshold as a part of the narcotic abstinence syndrome in rats. Psychopharmacologia, 35:243–247, 1974.CrossRefGoogle Scholar
  3. Andrews, H. L., and Himmelsbach, C. K. Relation of the intensity of the morphine abstinence syndrome to dosage. J. Pharmacol. Exp. Therap., 81:288–293, 1944.Google Scholar
  4. Bhargava, H. N., and Way, E. L. Morphine tolerance and physical dependence: influence of cholinergic agonists and antagonists. Eur. J. Pharmacol., 36:79–88, 1976.CrossRefGoogle Scholar
  5. Branchey, M., Rauscher, G., and Kissin, B. Modifications in the response to alcohol following the establishment of physical dependence. Psychopharmacologia, 22:314–322, 1971.CrossRefGoogle Scholar
  6. Cardenas, H., and Ross, D. H. Morphine induced calcium depletion in discrete regions of rat brain. J. Neurochem., 24:487–493, 1975.CrossRefGoogle Scholar
  7. Carder, B., and Olson, J. Learned behavioral tolerance to marihuana in rats. Pharmacol. Biochem. Behav., 1:73–76, 1973.CrossRefGoogle Scholar
  8. Chen, C. -S. A study of the alcohol-tolerance effect and an introduction of a new behavioural technique. Psychopharmacologia, 12:433–440, 1968.CrossRefGoogle Scholar
  9. Cochin, J., and Kornetsky, C. Development and loss of tolerance to morphine in the rat after single and multiple injections. J. Pharmacol. Exp. Therap., 145:1–10, 1964.Google Scholar
  10. Cox, B. M., and Osman, O. H. Inhibition of the development of tolerance to morphine in rats by drugs which inhibit ribonucleic acid or protein synthesis. Brit. J. Pharmacol., 38:157–170, 1970.CrossRefGoogle Scholar
  11. Crossland, J. Acetylcholine and morphine dependence. In H. W. Kosterlitz, H. O. J. Collier and J. E. Villareal (Eds.) Agonist and Antagonist Actions of Narcotic Analgesic Drugs, pp. 232–234. Baltimore, University Park Press, 1973.Google Scholar
  12. Ellis, F. W., and Pick, J. R. Dose- and time-dependent relationships in ethanol-induced withdrawal reactions. Fed. Proc, 30: 568, 1971.Google Scholar
  13. Erickson, C. K., and Chai, K. J. Cholinergic modification of ethanol-induced electroencephalographic synchrony in the rat. Neuro-pharmacol., 15:39–43, 1976.CrossRefGoogle Scholar
  14. Essig, C. F. Barbiturate withdrawal convulsions in decerebellate dogs. Int. J. Neuropharmacol., 3 : 453–456, 1964.CrossRefGoogle Scholar
  15. Feinberg, M. P., and Cochin, J. Inhibition of development of tolerance to morphine by cycloheximide. Biochem. Pharmacol., 21: 3082–3085, 1972.CrossRefGoogle Scholar
  16. Fink, M. Electrophysiology of drugs of dependence. In S. J. Mule and H. Brill (Eds.) Chemical and Biological Aspects of Drug Dependence, pp. 379–387. Cleveland, CRC Press, 1972.Google Scholar
  17. Fink, M., Zaks, A., Volavka, J., and Roubicek, J. Opiates and antagonists (Electrophysiological studies in man). In D. H. Clouet (Ed.) Narcotic Drugs: Biochemical Pharmacology, pp. 452–467. New York, Plenum Press, 1971.Google Scholar
  18. Frankel, D., Khanna, J. M., LeBlanc, A. E., and Kalant, H. Effect of p-chlorophenylalanine on the acquisition of tolerance to ethanol and pentobarbital. Psychopharmacologia, 44:247–252, 1975.CrossRefGoogle Scholar
  19. Frederickson, R. C. A. Morphine withdrawal response and central cholinergic activity. Nature, 257:131–132, 1975.CrossRefGoogle Scholar
  20. Gibbins, R. J., Kalant, H., LeBlanc, A. E., and Clark, J. W. The effects of chronic administration of ethanol on startle thresholds in rats. Psychopharmacologia, 19:95–104, 1971.CrossRefGoogle Scholar
  21. Gispen, W. H., Krivoy, W. A., deWied, D., and Zimmerman, E. Effect of rifampicin on development of tolerance to analgesic actions of morphine. Life Sci., 17:247–252, 1975.CrossRefGoogle Scholar
  22. Goldstein, A. Opiate receptors. Life Sci., 14 :615–623, 1974.CrossRefGoogle Scholar
  23. Goldstein, D. Relationship of alcohol dose to intensity of withdrawal signs in mice. J. Pharmacol. Exp. Therap., 180:203–215, 1972.Google Scholar
  24. Grenell, R. G., Mendelson, J., and McElroy, W. D. Neuronal metabolism and ATP synthesis in narcosis. J. Cell. Comp. Physiol., 46.: 143–161, 1955.CrossRefGoogle Scholar
  25. Himmelsbach, C. K., and Andrews, H. L. Studies on modification of the morphine abstinence syndrome by drugs. J. Pharmacol. Exp. Therap., 77:17–23, 1943.Google Scholar
  26. Hunter, B. E., Riley, J., Walker, D. W., and Freund, G. Ethanol dependence in the rat: a parametric analysis. Pharmacol. Biochem. Behav., 2:619–629, 1975.CrossRefGoogle Scholar
  27. Isbell, H., Altschul, S., Kornetsky, C. H., Eisenman, A. J., Flanary, H. G., and Fraser, H. F. Psychological effects of chronic barbiturate intoxication. Arch. Neurol. Psychiat., 65:557–567, 1951.CrossRefGoogle Scholar
  28. Iwamoto, E. T., Loh, H. H., and Way, E. L. Dopaminergic-cholinergic interactions in naloxone-induced circling in morphine-dependent rats with nigral lesions. Eur. J. Pharmacol., 38:39–54, 1976.CrossRefGoogle Scholar
  29. Johanneson, T., and Steele, W. J. Actinomycin D and development of tolerance to morphine analgesia in rats. Acta Pharmacol. Toxicol., 32:519–524, 1973.CrossRefGoogle Scholar
  30. Kalant, H. Direct effects of ethanol on the nervous system. Fed. Proc, 34:1930–1941, 1975.Google Scholar
  31. Kalant, H., and Grose, W. Effects of ethanol and pentobarbital on release of acetylcholine from cerebral cortex slices. J. Pharmacol. Exp. Therap., 158:386–393, 1967.Google Scholar
  32. Kalant, H., LeBlanc, A. E., and Gibbins, R. J. Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmacol. Rev., 23:135–191, 1971.Google Scholar
  33. Kayan, S., Ferguson, R. K., and Mitchell, C. L. An investigation of pharmacologic and behavioral tolerance to morphine in rats. J. Pharmacol. Exp. Therap., 185:300–306, 1973.Google Scholar
  34. Kayan, S., and Mitchell, C. L. The role of the dose-interval on the development of tolerance to morphine. Arch. Int. Pharmacodyn. Therap., 198:238–241, 1972.Google Scholar
  35. Kayan, S., Woods, L. A., and Mitchell, C. L. Experience as a factor in the development of tolerance to the analgesic effect of morphine. Eur. J. Pharmacol., 6:333–339, 1969.CrossRefGoogle Scholar
  36. Kornetsky, C., and Bain, G. Morphine: single-dose tolerance. Science, 162:1011–1012, 1968.CrossRefGoogle Scholar
  37. Laschka, E., Teschemacher, H., Mehraein, P., and Herz, A. Sites of action of morphine involved in the development of physical dependence in rats. Psychopharmacologia, 46:141–147, 1976.CrossRefGoogle Scholar
  38. LeBlanc, A. E., Gibbins, R. J., and Kalant, H. Behavioral augmentation of tolerance to ethanol in the rat. Psychopharmacologia, 30:117–122, 1973.CrossRefGoogle Scholar
  39. LeBlanc, A. E., Gibbins, R. J., and Kalant, H. Generalization of behaviorally augmented tolerance to ethanol, and its relation to physical dependence. Psychopharmacologia, 44:241–246, 1975.CrossRefGoogle Scholar
  40. LeBlanc, A. E., Matsunaga, M., and Kalant, H. Effects of frontal polar cortical ablation and cycloheximide on ethanol tolerance in rats. Pharmacol. Biochem. Behav., 4:175–179, 1976.CrossRefGoogle Scholar
  41. Loh, H. H., Shen, F.-H., and Way, E. L. Inhibition of morphine tolerance and physical dependence development and brain serotonin synthesis by cycloheximide. Biochem. Pharmacol., 18:2711–2721, 1969.CrossRefGoogle Scholar
  42. McQuarrie, D. G., and Fingl, E. Effects of single doses and chronic administration of ethanol on experimental seizures in mice. J. Pharmacol. Exp. Therap., 124:264–271, 1958.Google Scholar
  43. Mucha, R. F., Pinel, J. P. J., and Van Oot, P. H. Simple method for producing an alcohol withdrawal syndrome in rats. Pharmacol. Biochem. Behav., 3:765–769, 1975.CrossRefGoogle Scholar
  44. Mushlin, B. E., Grell, R., and Cochin, J. Studies on tolerance. I. The role of the interval between doses on the development of tolerance to morphine. J. Pharmacol. Exp. Therap., 196: 280–287, 1976.Google Scholar
  45. Mycek, M. J., and Brezenoff, H. E. Tolerance to centrally administered phenobarbital. Biochem. Pharmacol., 25:501–504, 1976.CrossRefGoogle Scholar
  46. Quastel, J. H. Effects of drugs on metabolism of the brain in vitro. Brit. Med. Bull., 21:49–56, 1965.Google Scholar
  47. Ross, D. H., Medina, M. A., and Cardenas, H..L. Morphine and ethanol: selective depletion of regional brain calcium. Science, 186: 63–65, 1974.CrossRefGoogle Scholar
  48. Sharpless, S. K., and Jaffe, J. H. The electrical excitability of isolated cortex during barbiturate withdrawal. J. Pharmacol. Exp. Ther., 151:321–329, 1966.Google Scholar
  49. Siegel, S. Evidence from rats that morphine tolerance is a learned response. J. Comp. Physiol. Psychol., 89:498–506, 1975.CrossRefGoogle Scholar
  50. Takemori, A. E. Intermediary and energy metabolism. In D. H. Clouet (Ed.) Narcotic Drugs: Biochemical Pharmacology, pp. 159–189. New York, Plenum Press, 1971.Google Scholar
  51. Theiss, P., Papeschi, R., and Herz, A. Effects of morphine on the turnover of brain catecholamines and serotonin in rats — chronic morphine administration. Eur. J. Pharmacol., 34:263–271, 1975.CrossRefGoogle Scholar
  52. Tilson, H. A., and Rech, R. H. The effects of p-chlorophenylalanine on morphine analgesia, tolerance and dependence development in two strains of rats. Psychopharmacologia, 25::45–60, 1974.CrossRefGoogle Scholar
  53. Wahlström, G., and Ekwall, T. Tolerance to hexobarbital and supersensitivity to pilocarpine after chronic barbital treatments in the rat. Eur. J. Pharmacol., 38:123–129, 1976.CrossRefGoogle Scholar
  54. Waters, D. H., and Okamoto, M. Increased central excitability in non-dependent mice during chronic barbital dosing. In J. M. Singh, L. Miller and H. Lai (Eds.) Drug Addiction, Vol. 1, Experimental Pharmacology, pp. 199–209. Mt. Kisco, N.Y., Futura, 1976.Google Scholar
  55. Way, E. L., Loh, H. H., and Shen, F.-H. Morphine tolerance, physical dependence and synthesis of brain 5-hydroxytryptamine. Science, 162: 1290–1292, 1968.CrossRefGoogle Scholar
  56. Way, E. L., and Shen, F.-H. Catecholamines and 5-hydroxytryptamine. In D. H. Clouet (Ed.) Narcotic Drugs: Biochemical Pharmacology, pp. 229–253. New York, Plenum Press, 1971.Google Scholar
  57. Weinstock, M. Acetylcholine and Cholinesterase. In D. H. Clouet, D. H. Clouet (Ed.) Narcotic Drugs: Biochemical Pharmacology , pp. 254–261.Google Scholar
  58. Wikler, A. Opiate Addiction. Psychological and Neurophysiological Aspects in Relation to Clinical Problems. Springfield, Illinois, C. C. Thomas, 1953. Chapters 5 and 6.Google Scholar
  59. Wikler, A., Fraser, H. F., Isbell, H., and Pescor, F. T. Electroencephalograms during cycles of addiction to barbiturates in man. Electroenceph. Clin. Neurophysiol., 7:1–13 1955.CrossRefGoogle Scholar
  60. Wikler, A., Pescor, F. T., Fraser, H. F., and Isbell, H. Electro-encephalographic changes associated with chronic alcoholic intoxication and alcohol abstinence syndrome. Amer. J. Psychiat., 113:106–114, 1956.Google Scholar

Copyright information

© Plenum Press, New York 1977

Authors and Affiliations

  • H. Kalant
    • 1
    • 2
  1. 1.Department of PharmacologyUniversity of TorontoTorontoCanada
  2. 2.Addiction Research Foundation of OntarioTorontoCanada

Personalised recommendations