, Volume 36, Issue 3, pp 243–253 | Cite as

Morphine and δ9-tetrahydrocannabinol: Tolerance to the stimulus effects

  • Ira D. Hirschhorn
  • John A. Rosecrans
Animal Studies


Morphine and saline served as discriminative Stimuli for one group of rats in a 2-lever discrimination task. δ9-THC and vehicle were discriminative stimuli for a second group. Depression of one lever resulted in reinforcement following the administration of morphine or δ9-THC and the opposite lever was reinforced after vehicle. A high degree of discriminated responding occurred with both drugs. During daily supplemental injections of morphine or δ9-THC up to several times the training dose for a period of 2 months, subjects still discriminated morphine or δ9-THC from vehicle. However, the degree of discrimination was reduced indicating a limited tolerance to either drug. Naloxone precipitated narcoticlike withdrawal symptoms in rats chronically treated with either morphine or δ9-THC, indicating that there is an interaction between chronic administration of δ9-THC and the narcotic antagonist, naloxone.

Key words

Morphine δ9-Tetrahydrocannabinol (δ9-THC) Tolerance Physical Dependence Withdrawal Naloxone Discriminative Stimulus 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Barry, H., Kubena, R. K.: Repeated high doses of δ 9-tetrahydrocannabinol enhanced acquisition of shock avoidance by rats. Proc. Amer. Psychol. Ass. 6, 747–748 (1971)Google Scholar
  2. Bueno, O. F. A., Carlini, E. A.: Dissociation of learning in marihuana tolerant rats. Psychopharmacologia (Berl.) 25, 49–56 (1972)Google Scholar
  3. Cochin, J., Kornetsky, C.: Development and loss of tolerance to morphine in the rat after single and multiple injections. J. Pharmacol. exp. Ther. 145, 1–10 (1964)Google Scholar
  4. Cradock, J. C., Davignon, J. P., Litterst, C. L., Guarino, A. M.: An intravenous formulation of δ 9-tetrahydrocannabinol using a non-ionic surfactant. J. Pharm. Pharmacol. 25, 345 (1973)Google Scholar
  5. Deneau, G. A., Kaymakcalan, S.: Physiological and psychological dependence to synthetic δ 9-tetrahydrocannabinol (THC) in rhesus monkeys. Pharmacologist 13, 308 (1971)Google Scholar
  6. Ferraro, D. P., Grilly, D. M.: Lack of tolerance to δ 9-tetrahydrocannabinol in chimpanzees. Science 179, 490–492 (1973)Google Scholar
  7. Gebhart, G. E., Sherman, A. P., Mitchell, C. L.: The influence of stress on tolerance development to morphine in rats tested on the hot plate. Arch. int. Pharmacodyn. 197, 328–337 (1972)Google Scholar
  8. Goldstein, A., Aronow, L., Kalman, S. M.: Principles of drug action. New York: Hoeber 1969Google Scholar
  9. Goodman, L. S., Gilman, A.: The pharmacological basis of therapeutics. New York: MacMillan 1970Google Scholar
  10. Hirschhorn, I. D., Winter, J. C.: Mescaline and lyseric acid diethylamide (LSD) as discriminative stimuli. Psychopharmacologia (Berl.) 22, 64–71 (1971)Google Scholar
  11. Hirschhorn, I. D., Rosecrans, J. A.: Nicotine as a discriminative stimulus: the time course of the cue and the effect of receptor blockers. Pharmacologist 15, 452 (1973)Google Scholar
  12. Hill, H. E., Jones, B. E., Bell, E. L.: State-dependent control of discrimination by morphine and pentobarbitol. Psychopharmacologia (Berl.) 22, 305–313 (1971)Google Scholar
  13. Hollister, L. E., Tinklenberg, J. R.: Subchronic oral doses of marijuana extract. Psychopharmacologia (Berl.) 29, 247–252 (1973)Google Scholar
  14. Kamaei, C., Shimomura, K., Veki, S.: Significance of withdrawal jumping response in predicting physical dependence in mice. Japan J. Pharmacol. 23, 421–426 (1973)Google Scholar
  15. Kubena, R. K., Barry, H.: Generalization of alcohol and atropine stimulus characteristics to other drugs. Psychopharmacologia (Berl.) 15, 196–206 (1969)Google Scholar
  16. Kubena, R. K., Barry, H.: Stimulus characteristics of marijuana components. Nature (Lond.) 235, 397–398 (1972)Google Scholar
  17. Martin, W. R., Fraser, H. F.: A comparative study of physiological and subjective effects of heroin and morphine administered intravenously in postaddicts. J. Pharmacol. exp. Ther. 133, 388–399 (1961)Google Scholar
  18. McGuigan, G. J.: Experimental psychology, a methodological approach. Englewood Cliffs: Prentice-Hall 1968Google Scholar
  19. McMillan, D. E., Harris, L. S., Frankenheim, J. M., Kennedy, J. S.: 1-δ 9-trans-tetrahydrocannabinol in pigeons: tolerance to the behavioral effects. Science 169, 501–503 (1970)Google Scholar
  20. Overton, D. A.: Dissociated learning in drug states (state dependent learning). In: Psychopharmacology, A review of progress, 1957–1967, pp. 918–930. D. H. Efron, Ed. Washington: U. S. Government Printing Office 1968Google Scholar
  21. Overton, D. A.: Discriminative control of behavior by drug states. In: stimulus properties of drugs, T. Thompson, R. Pickens, Ed. New York: Appleton-Century-Crofts 1971Google Scholar
  22. Rosecrans, J. A., Goodloe, M. H., Bennett, G. J., Hirschhorn, I. D.: Morphine as a discriminative cue: effects of amine depletors and naloxone. Europ. J. Pharmacol. 21, 252–256 (1973)Google Scholar
  23. Williams, E. G., Himmelsbach, C. K., Wikler, A., Ruble, D. C., Lloyd, B. J.: Studies on marijuana and pyrahexyl compound. Publ. Hlth Rep. (Wash.) 61, 1059–1083 (1946)Google Scholar
  24. Way, E. L., Loh, H. H., Shen, F. H.: Simultaneous quantitative assessment of morphine tolerance and physical dependence. J. Pharmacol. exp. Ther. 167, 1–8 (1969)Google Scholar

Copyright information

© Springer-Verlag 1974

Authors and Affiliations

  • Ira D. Hirschhorn
    • 1
  • John A. Rosecrans
    • 1
  1. 1.Department of PharmacologyMedical College of VirginiaRichmond

Personalised recommendations