Skip to main content
SpringerLink
Log in

Effects of repeated doses of l-δ8-trans-tetrahydrocannabinol on schedule-controlled temporally-spaced responding of rats

  • Published:
Psychopharmacologia Aims and scope Submit manuscript

Abstract

The effects have been observed of chronic daily intraperitoneal injections of a marijuana (cannabis) constituent, δ 8-tetrahydrocannabinol (δ 8-THC), on the temporally-spaced lever pressing of rats maintained under a DRL (differential reinforcement of low rates of responding) schedule of water reinforcement. A different chronic dose was given to each of four rats. During the test session following the first drug injection, the two rats which received the lower doses (5.62 or 10.0 mg/kg) showed lengthy periods of no lever pressing, and the two rats receiving the higher doses (17.8 or 31.6 mg/kg) showed almost no lever pressing. In the case of the lower doses, the response rate between the long pauses was increased. With repeated injections, tolerance developed to the drug-induced cessation of responding at all dose levels, but increased sensitivity to the response rate-increasing effect was observed, particularly with the 10.0 and 17.8 mg/kg doses. These behavioral effects were probably not mediated by drug-induced changes in body temperature regulation. The increased sensitivity to the rate-increasing effect of the marijuana constituent with repeated injection may be related to the “reverse tolerance” to marijuana's psychological effects that has been reported in man.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anger, D.: The dependence of interresponse times upon the relative reinforcement of different interresponse times. J. exp. Psychol. 52, 145–161 (1956)

    Google Scholar 

  • Bailey, P. T., Pradhan, S. N.: Effects of δ 9-tetrahydrocannabinol and mescaline on self-stimulation. Neuropharmacol. 11, 831–838 (1972)

    Google Scholar 

  • Black, M. B., Woods, J. H., Domino, E. F.: Some effects of (−)δ 9-trans-tetrahydrocannabinol and other cannabis derivatives on schedule controlled behavior. Pharmacologist 12, 258 (1970)

    Google Scholar 

  • Boyd, E. S., Hutchinson, E. D., Gardner, L. C., Meritt, D. A.: Effects of tetrahydrocannabinols and other drugs on operant behavior in rats. Arch. int. Pharmacodyn. 144, 533–554 (1963)

    Google Scholar 

  • Bueno, O. F. A., Carlini, E. A.: Dissociation of learning in marihuana-tolerant rats. Psychopharmacologia (Berl.) 25, 49–56 (1972)

    Google Scholar 

  • Campo, R. A.: Development of tolerance in pigeons to behavioral effects of a new benzopyran derivative. J. Pharmacol. exp. Ther. 184, 521–527 (1973)

    Google Scholar 

  • Carlini, E. A.: Tolerance to chronic administration of Cannabis sativa (marihuana) in rats. Pharmacology 1, 135–142 (1968)

    Google Scholar 

  • Carlini, E. A.: Acute and chronic behavioral effects of Cannabis sativa. In: Pharmacology and the future of man. Proceedings of the 5th International Congress on Pharmacology, San Francisco 1972, vol. 1, pp. 31–43. Basel: Karger 1973

    Google Scholar 

  • Dagirmanjian, R., Boyd, E. S.: Some pharmacological effects of two tetrahydro-cannabinols. J. Pharmacol. exp. Ther. 135, 25–33 (1962)

    Google Scholar 

  • Dewey, W. L., Harris, L. S., Howes, J. F., Kennedy, J. S., Granchelli, F. E., Pars, H. G., Razdan, R. K.: Pharmacology of some marijuana constituents and two heterocyclic analogues. Nature (Lond.) 226, 1265–1267 (1970)

    Google Scholar 

  • Dewey, W. L., McMillan, D. E., Harris, L. S., Turk, R. F.: Distribution of radioactivity in brain of tolerant and nontolerant pigeons treated with 3H-δ 9-tetrahydrocannabinol. Biochem. Pharmacol. 22, 399–405 (1973)

    Google Scholar 

  • Dingell, J. V., Owens, M. L., Norvich, M. R., Sulser, F.: On the role of norepinephrine biosynthesis in the central action of amphetamine. Life Sci. 6, 1155–1162 (1967)

    Google Scholar 

  • Drew, W. G., Miller, L. L., Wikler, A.: Effect of δ 9-THC on the open field activity of the rat. Psychopharmacologia (Berl.) 23, 289–299 (1972)

    Google Scholar 

  • Ferraro, D. P., Grilly, D. M., Lynch, W. C.: Effects of marihuana extract on the operant behavior of chimpanzees. Psychopharmacologia (Berl.) 22, 333–351 (1971)

    Google Scholar 

  • Ferraro, D. P., Grisham, M. G.: Tolerance to the behavioral effects of marihuana in chimpanzees. Physiol. Behav. 9, 49–54 (1972)

    Google Scholar 

  • Fox, M. N.: Cannabis and reverse tolerance: Pharmacological entity or psychological phenomenon? Med. J. Aust. 2, 863–865 (1973)

    Google Scholar 

  • Frankenheim, J. M., McMillan, D. E., Harris, L. S.: Effects of l-δ 9- and l-δ 8-trans-tetrahydrocannabinol and cannabinol on schedule-controlled behavior in pigeons and rats. J. Pharmacol. exp. Ther. 178, 241–252 (1971)

    Google Scholar 

  • Garriott, J. C., King, L. J., Forney, R. B., Hughes, F. W.: Effects of some tetrahydrocannabinols on hexobarbital sleeping time and amphetamine induced hyperactivity in mice. Life Sci. 6, 2119–2128 (1967)

    Google Scholar 

  • Gershon, S.: On the pharmacology of marihuana. Behav. Neuropsychiat. 1, 9–18 (1970)

    Google Scholar 

  • Gill, E. W., Paton, W. D. M., Pertwee, R. G.: Preliminary experiments on the chemistry and pharmacology of cannabis. Nature (Lond.) 228, 134–136 (1970)

    Google Scholar 

  • Grunfeld, Y., Edery, H.: Psychopharmacological activity of the active constituents of hashish and some related cannabinoids. Psychopharmacologia (Berl.) 14, 200–210 (1969)

    Google Scholar 

  • Hardman, H. F., Domino, E. F., Seevers, M. H.: General pharmacological actions of some synthetic tetrahydrocannabinol derivatives. Pharmacol. Rev. 23, 295–315 (1971)

    Google Scholar 

  • Hively, R. L., Mosher, W. A., Hoffman, F.: Isolation of trans-δ 6-tetrahydrocannabinol from marihuana. J. Amer. chem. Soc. 88, 1832–1833 (1966)

    Google Scholar 

  • Ho, B. T., Taylor, D., Englert, L. F.: The effect of repeated administration of (−)-δ-9-tetrahydrocannabinol on the biosynthesis of brain amines. Res. Commun, chem. Path. Pharmacol. 5, 851–854 (1973)

    Google Scholar 

  • Holz, W. C., Azrin, N. H., Ulrich, R. E.: Punishment of temporally spaced responding. J. exp. Anal. Behav. 6, 115–122 (1963)

    Google Scholar 

  • Interim Report of the Canadian Government Commission of Inquiry: The nonmedical use of drugs. London: Penguin 1970

  • Jaffe, J. H.: Drug addiction and drug abuse. In: The Pharmacological Basis of Therapeutics. L. S. Goodman and A. Gilman, Eds., Fourth Edition, pp. 276 to 313. New York: Macmillan 1970

    Google Scholar 

  • Keeler, M. H.: Motivation for marihuana use: A correlate of adverse reaction. Amer. J. Psychiat. 125, 386–390 (1968)

    Google Scholar 

  • Kelleher, R. T., Fry, W., Deegan, J., Cook, L.: Effects of meprobamate on operant behavior in rats. J. Pharmacol. exp. Ther. 133, 271–280 (1961)

    Google Scholar 

  • Kubena, R. K., Barry, H., III.: Interactions of δ 1-tetrahydrocannabinol with barbiturates and methamphetamine. J. Pharmacol. exp. Ther. 173, 94–100 (1970)

    Google Scholar 

  • Laties, V. G., Weiss, B.: Effects of alcohol on timing behavior. J. comp. physiol. Psychol. 55, 85–91 (1962)

    Google Scholar 

  • Lomax, P.: Acute tolerance to the hypothermic effect of marihuana in the rat. Res. Commun. chem. Path. Pharmacol. 2, 159–167 (1971)

    Google Scholar 

  • Masur, J., MÄrtz, R. M. W., Carlini, E. A.: Effects of acute and chronic administration of Cannabis saliva and δ 9-THC on the behavior of rats in an open-field arena. Psychopharmacologia (Berl.) 19, 388–397 (1971)

    Google Scholar 

  • McMillan, D. E.: The effects of ethyl alcohol on temporally spaced responding in humans. J. Pharmacol. exp. Ther. 171, 159–165 (1970)

    Google Scholar 

  • McMillan, D. E., Dewey, W. L., Harris, L. S.: Characteristics of tetrahydrocannabinol tolerance. Ann. N. Y. Acad. Sci. 191, 83–96 (1971)

    Google Scholar 

  • McMillan, D. E., Dewey, W. L., Turk, R. F., Harris, L. S., McNeil, J. H., Jr.: Blood levels of 3H-δ 9-tetrahydrocannabinol and its metabolites in tolerant and nontolerant pigeons. Biochem. Pharmacol. 22, 383–397 (1973)

    Google Scholar 

  • McMillan, D. E., Ford, R. D., Frankenheim, J. M., Harris, R. A., Harris, L. S.: Tolerance to active constituents of marihuana. Arch. int. Pharmacodyn. 198, 132–144 (1972)

    Google Scholar 

  • McMillan, D. E., Harris, L. S., Frankenheim, J. M., Kennedy, J. S.: l-δ 9-trans-Tetrahydrocannabinol in pigeons: Tolerance to the behavioral effects. Science 169, 501–503 (1970)

    Google Scholar 

  • Mechoulam, R.: Marihuana chemistry. Science 168, 1159–1166 (1970)

    Google Scholar 

  • Mills, L., Brawley, P.: The psychopharmacology of “Cannabis sativa”: A review. Agents and Actions 2, 201–215 (1972)

    Google Scholar 

  • Randrup, A., Munkvad, I.: Role of catecholamines in the amphetamine excitatory response. Nature (Lond.) 211, 540 (1966)

    Google Scholar 

  • Reynolds, G. S.: Temporally spaced responding by pigeons: Development and effects of deprivation and extinction. J. exp. Anal. Behav. 7, 415–421 (1964)

    Google Scholar 

  • Reynolds, G. S., Catania, A. C.: Behavioral contrast with fixed-interval and low-rate reinforcement. J. exp. Anal. Behav. 4, 387–391 (1961)

    Google Scholar 

  • Richelle, M., Xhenseval, B., Fontaine, O., Thone, L.: Action of chlordiazepoxide on two types of temporal conditioning in rats. Int. J. Neuropharmacol. 1, 381–391 (1962)

    Google Scholar 

  • Robbins, T. W., Iversen, S. D.: Amphetamine-induced disruption of temporal discrimination by response disinhibition. Nature New Biol. 245, 191–192 (1973)

    Google Scholar 

  • Scheckel, C. L., Boff, E., Dahlen, P., Smart, T.: Behavioral effects in monkeys of racemates of two biologically active marijuana constituents. Science 160, 1467–1469 (1968)

    Google Scholar 

  • Schultes, R. E.: Hallucinogens of plant origin. Science 163, 245–254 (1969)

    Google Scholar 

  • Schuster, C. R., Zimmerman, J.: Timing behavior during prolonged treatment with dl-amphetamine. J. exp. Anal. Behav. 4, 327–330 (1961)

    Google Scholar 

  • Sidman, M.: Technique for assessing the effects of drugs on timing behavior. Science 122, 925 (1955)

    Google Scholar 

  • Sidman, M.: Time discrimination and behavioral interaction in a free operant situation. J. comp. physiol. Psychol. 49, 469–473 (1956a)

    Google Scholar 

  • Sidman, M.: Drug-behavior interaction. Ann. N. Y. Acad. Sci. 65, 282–302 (1956b)

    Google Scholar 

  • Siegel, R. K.: Effects of Cannabis sativa and lysergic acid diethylamide on a visual discrimination task in pigeons, Psychopharmacologia (Berl.) 15, 1–8 (1969)

    Google Scholar 

  • Silva, M. T. A., Carlini, E. A., Claussen, U., Korte, F.: Lack of cross-tolerance in rats among (−)δ 9-trans-tetrahydrocannabmol (δ 9-THC), cannabis extract, mescaline and lysergic acid diethylamide (LSD-25). Psychopharmacologia (Berl.) 13, 332–340 (1968)

    Google Scholar 

  • Sjödén, P. O., JÄrbe, T. U. C., Henriksson, B. G.: Effects of long-term administration and withdrawal of tetrahydrocannabinols (δ 8-THC and δ 9-THC) on open-field behavior in rats. Pharmacol. Biochem. Behav. 1, 243–249 (1973)

    Google Scholar 

  • Smythies, J. R., Johnston, V. S., Bradley, R. J.: Alteration by pretreatment with iproniazid and an inactive mescaline analogue of a behavior change induced by mescaline. Nature (Lond.) 216, 196–197 (1967)

    Google Scholar 

  • Waters, D. H., Glick, S. D.: Asymmetrical effect of delta-9-tetrahydrocannabinol (THC) on striatal dopamine and behavior. Res. Commun, chem. Path. Pharmacol. 6, 57–63 (1973)

    Google Scholar 

  • Webster, C. D., LeBlanc, A. E., Marshman, J. A., Beaton, J. M.: Acquisition and loss of tolerance to l-9-trans-tetrahydrocannabinol in rats on an avoidance schedule. Psychopharmacologia (Berl.) 30, 217–226 (1973)

    Google Scholar 

  • Webster, C. D., Willinsky, M. D., Herring, B. S., Walters, G. C.: Effects of l-δ1-tetrahydrocannabinol on temporally spaced responding and discriminated Sidman avoidance behaviour in rats. Nature (Lond.) 232, 498–501 (1971)

    Google Scholar 

  • Weil, A. T., Zinberg, N. E., Nelsen, J. M.: Clinical and psychological effects of marihuana in man. Science 162, 1234–1242 (1968)

    Google Scholar 

  • Weiss, B., Laties, V. G.: Comparative pharmacology of drugs affecting behavior. Fed. Proc. 26, 1146–1156 (1967)

    Google Scholar 

  • Weissman, A., Koe, B. K., Tenen, S. S.: Antiamphetamine effects following inhibition of tyrosine hydroxylase. J. Pharmacol. exp. Ther. 151, 339–352 (1966)

    Google Scholar 

  • Williams, E. G., Himmelsbach, C. K., Wikler, A., Ruble, D. C.: Studies on marihuana and pyrahexyl compound. Publ. Hlth Rep. 61, 1059–1083 (1946)

    Google Scholar 

  • Wilson, M. P., Keller, F. S.: On the selective reinforcement of spaced responses. J. comp. physiol. Psychol. 46, 190–193 (1953)

    Google Scholar 

  • Zimmerman, J., Schuster, C. R.: Spaced responding in multiple DRL schedules. J. exp. Anal. Behav. 5, 497–504 (1962)

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Western Australia, Australia

    Jerry M. Frankenheim

Authors
  1. Jerry M. Frankenheim
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Frankenheim, J.M. Effects of repeated doses of l-δ8-trans-tetrahydrocannabinol on schedule-controlled temporally-spaced responding of rats. Psychopharmacologia 38, 125–144 (1974). https://doi.org/10.1007/BF00426107

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00426107

Key words

Search

Navigation