Cannabinoid agonists and antagonists modulate lithium-induced conditioned gaping in rats

  • Linda A. Parker
  • Raphael Mechoulam


Considerable evidence indicates that conditioned gaping in rats reflects nausea in this species that does not vomit. A series of experiments evaluated the potential of psychoactive cannabinoid agonists, Δ-9-THC and HU-210, and non-psychoactive cannabinoids, Cannabidiol (CBD) and its dimethylheptyl homolog (CBD-dmh), to interfere with the establishment and the expression of conditioned gaping in rats. All agents attenuated both the establishment and the expression of conditioned gaping. Furthermore, the CB1 antagonist, SR-141716, reversed the suppressive effect of HU-210 on conditioned gaping. Finally, SR-141716 potentiated lithium-induced conditioned gaping, suggesting that the endogenous cannabinoid system plays a role in the control of nausea.

Key words

classical conditioning nausea emesis taste avoidance learning taste aversion learning cannabinoids taste reactivity 


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  1. Berridge, K.C., Grill, H.J. & Norgren, R. (1981). Relation of consummatory responses and preabsorptive insulin release to palatability and learned taste aversions.Journal of Comparative and Physiological Psychology, 95, 363–82.PubMedCrossRefGoogle Scholar
  2. Blackshaw, L.A. & Grundy, D. (1993). Effects of 5-hydroxytryptamine on discharge of vagal mucosal afferent fibres from the upper gastrointestinal tract of the ferret.Journal of the Autonomic Nervous System, 45, 41–50.PubMedCrossRefGoogle Scholar
  3. Cordick, N., Parker, L.A. & Ossenkopp, K.P. (1999). Rotation-induced conditioned rejection in the taste reactivity test.NeuroReport, 10, 1157–1159.CrossRefGoogle Scholar
  4. Darmani, N.A. (2001a). Delta-9-tetrahydrocannabinol and synthetic cannabinoids prevent emesis produced by the cannabinoid CB1 receptor antagonist/inverse agonist SR-41716A.Neuropsychopharmacology, 24, 198–203.PubMedCrossRefGoogle Scholar
  5. Darmani, N.A. (2001b). Delta-9-tetrahydrocannabinol differentially suppresses cisplatin-induced emesis and indices of motor function via cannabinoid CB1 receptors in the least shrew.Pharmacology Biochemistry and Behavior, 69, 239–249.CrossRefGoogle Scholar
  6. Darmani, N.A. (2001c). The cannabinoid CB1 receptor antagonist SR 141716A reverses the antiemetic and motor depressant actions of WIN 55,212-2.European Journal of Pharmacology, 430, 49–58.PubMedCrossRefGoogle Scholar
  7. Darmani, N.A. (2002). The potent emetogenic effects of the endocannabinoid, 2-AG (2-arachidonoylglycerol) are blocked by delta(9)-tetrahydrocannabinol and other cannabinoids.Journal of Pharmacology and Experimental Therapeutics, 300, 34–42.PubMedCrossRefGoogle Scholar
  8. Davis, C.J., Harding, R.K., Leslie, R.A. & Andrews, P.L.R. (1986). The organisation of vomiting as a protective reflex. In: Davis, C.J., Lake-Bakaar, G.V., Grahame-Smith, D.G. (Eds.),Nausea and vomiting: mechanisms and treatment (pp. 65–75). Berlin: Springer-Verlag.Google Scholar
  9. Devane, W.A., Hanus, L., Breuer, A., Pertwee, R.G., Stevenson, L.A., Griffin, G., Gibson, D., Mandelbaum, A., Etinger, A. & Mechoulam, R. (1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor.Science, 258, 1946–1949.PubMedCrossRefGoogle Scholar
  10. Feigenbaum, J.J., Richmond, S.A., Weissman, Y. & Mechoulam, R. (1989). Inhibition of cisplatin-induced emesis in the pigeon by a non-psychotropic synthetic cannabinoid.European Journal of Pharmacology, 4, 159–165.CrossRefGoogle Scholar
  11. Ferrari, F., Ottani, A. & Giuliani, D. (1999). Cannabimimetic acitivity in rats and pigeons of HU-210, a potent antiemetic drug.Pharmacology, Biochemistry and Behavior, 62, 75–80.CrossRefGoogle Scholar
  12. Garcia, J. (1989). Food for Tolman: Cognition and cathexis in concert. In T. Archer & L-G. Nilsson (Eds.)Aversion, Avoidance and Anxiety (pp. 45–85). Hillsdale, NJ: Lawrence Erlbaum Associates, Inc.Google Scholar
  13. Grill, H.C. & Norgren, R. (1978). The taste reactivity test. I: Mimetic responses to gustatory stimuli in neurologically normal rats.Brain Research, 143, 263–79.PubMedCrossRefGoogle Scholar
  14. Hampson, A.J., Grimaldi, M., Axelrod, J. (1998). Cannabidiol and delta-9-tetrahydrocannabinol are neuroprotective antioxidants.Proceedings of the National Academy of Science, USA, 95, 8268–8273.CrossRefGoogle Scholar
  15. Hanus, L., Abu-Lafi, S., Fride, E., Breuer, A., Vogel, Z., Shalev, D.E., Kustanovick, I., & Mechoulam, R. (2001). 2-Arachidonoyl glycerol ether, endogenous agonist of the cannabinoid CB1 receptor.Proceedings of the National Academy of Science, USA, 98, 3662–3665.CrossRefGoogle Scholar
  16. Jin, K.L., Mao, X.O., Goldsmith, P.C. & Greenberg, D.A. (2000). CB1 cannabinoid receptor induction in experimental stroke.Annals of Neurology, 48, 257–261.PubMedCrossRefGoogle Scholar
  17. Konorski, J. (1967).Integrative activity of the brain: An interdisciplinary approach. University of Chicago Press: Chicago.Google Scholar
  18. Limebeer, C.L. & Parker, L.A. (1999). Delta-9-tetrahydrocannabinol interferes with the establishment and the expression of conditioned disgust reactions produced by cyclophoshamide: A rat model of nausea.NeuroReport, 10, 3769–3772.PubMedCrossRefGoogle Scholar
  19. Limebeer, C.L. & Parker, L.A. (2000). Ondansetron interferes with the establishment and the expression of conditioned disgust reactions: A rat model of nausea.Journal of Experimental Psychology: Animal Behavior Processes, 26, 371–384.PubMedCrossRefGoogle Scholar
  20. Lowe, S. (1946). Studies on the pharmacology and acute toxicity of compounds with marihuana activity.Journal of Pharmacology and Experimental Therapeutics, 88, 154–161.Google Scholar
  21. Mallet, P.E. & Beninger, R.J. (1998). D-9-tetrahydrocannabinol, but not the endogenous cannabinoid receptor ligand, anandamide, produces conditioned place avoidance.Life Sciences, 62, 2431–2439.PubMedCrossRefGoogle Scholar
  22. McCarthy, L.E. & Borison, H.L. (1984). Cisplatin-induced vomiting eliminated by ablation of the area postrema in cats.Cancer Treatment Reports, 68, 401–404.PubMedGoogle Scholar
  23. McDonald, R.V., Parker, L.A. and Siegel, S. (1997). Conditioned sucrose aversions produced by naloxone-precipitated withdrawal from acutely administered morphine.Pharmacology, Biochemistry and Behavior, 58, 1–6.CrossRefGoogle Scholar
  24. Mechoulam, R., Ben-Shabat, S., Hanus, L., Ligumsky, M., Kaminski, N.E., Schatz, A.R., Gopher, A., Almog, S., Martin, B.R., Compton, D.R., Pertwee, R.G., Griffin, G., Bayewitch, M., Marg, J., & Vogel, Z. (1995). Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors.Biochemical Pharmacology, 50, 83–90.PubMedCrossRefGoogle Scholar
  25. Ossenkopp, K-P, Parker, L.A., Limebeer, C.L., Burton, P. and Cross-Mellor, S.K. (in press). Vestibular lesions selectively abolish rotation-induced, but not lithium-induced, conditioned taste aversions (oral rejection responses) in rats.Behavioral Neuroscience.Google Scholar
  26. Parker, L.A. (1982). Nonconsummatory and consummatory behavioral CRs elicited by lithium- and amphetamine-paired flavors.Learning and Motivation, 13, 281–303.CrossRefGoogle Scholar
  27. Parker, L.A. (1991). Taste reactivity responses elicited by reinforcing drugs: A dose-response analysis.Behavioral Neuroscience, 105, 955–964.PubMedCrossRefGoogle Scholar
  28. Parker, L.A. (1995). Rewarding drugs produce taste avoidance, but not taste aversion.Neuroscience and Biobehavioral Reviews, 19, 143–51.PubMedCrossRefGoogle Scholar
  29. Parker, L.A. (1998). Emetic drugs produce conditioned rejection reactions in the taste reactivity test.Journal of Psychophysiology, 12, 3–13.Google Scholar
  30. Parker, L.A. (2003). Taste avoidance and taste aversion: Evidence for two independent processes.Learning and Behavior.Google Scholar
  31. Parker, L.A. & Brosseau, L. (1990). Apomorphine-induced flavor-drug associations: A dose-response analysis by the taste reactivity test and the conditioned taste avoidance test.Pharmacology, Biochemistry and Behavior, 35, 583–87.CrossRefGoogle Scholar
  32. Parker, L.A. & Gillies, T. (1995). THC-induced place and taste aversions in Lewis and Sprague-Dawley rats.Behavioral Neuroscience, 109, 71–78.PubMedCrossRefGoogle Scholar
  33. Parker, L.A. & Kemp, S.W.P. (2001). Tetrahydrocannabinol (THC) interferes with conditioned retching inSuncus murinus: An animal model of anticipatory nausea and vomiting (ANV).NeuroReport, 12, 749–751.PubMedCrossRefGoogle Scholar
  34. Parker, L.A. & McLeod, K.B. (1991). Chin rub CRs may reflect conditioned sickness elicited by a lithiumpaired sucrose solution.Pharmacology, Biochemistry and Behavior, 40, 983–86.CrossRefGoogle Scholar
  35. Parker, L.A., Mechoulam, R. & Schlievert, C (2002). Cannabidiol, a non-psychoactive component of cannabis and its dimethylheptyl homolg suppress nausea in an experimental model with rats.NeuroReport, 13, 567–570.PubMedCrossRefGoogle Scholar
  36. Parker, L.A., Mechoulam, R., Schlievert, C., Abbott, L., Fudge, M.L. & Burton, P. (2003). Effects of cannabinoids on lithium-induced conditioned rejection reactions in a rat model of nausea.Psychopharmacology.Google Scholar
  37. Parker, L.A., Kwaitkowska, M., Burton, P. & Mechoulam, R. (in press). Effect of cannabinoids on lithiuminduced vomiting in theSuncus murinus (house musk shrew).Psychopharmacology.Google Scholar
  38. Pelchat, M.L., Grill, H.J., Rozin, P. & Jacobs, J. (1983). Quality of acquired responses to tastes byRattus norvegicus depends on type of associated discomfort.Journal of Comparative Psychology, 97, 140–53.PubMedCrossRefGoogle Scholar
  39. Rudd, J.A., Ngan, M.P. & Wai, M.K. (1998). 5-HT3 receptors are not involved in conditioned taste aversions induced by 5-hydroxytryptamine, ipecacuanha or cisplatin.European Journal of Pharmacology, 352, 143–149.PubMedCrossRefGoogle Scholar
  40. Sallen, S.E., Zinberg, N.E. & Frei, III E. (1975). Antiemetic effect of delt-9-tetrahydrocannabinol in patients receiving cancer chemotherapy.New England Journal of Medicine, 293, 795–98.CrossRefGoogle Scholar
  41. Schmid, P.C., Krebsbach, R.J., Perry, S.R., Dettmer, T.M., Masson, J.L., & Schmid, H.H. (1995). Occurrence and postmortem, generation of anandamide and other long-chain N-acylethanolamines in mammalian brain.FEBS Letters, 375, 117–120.PubMedCrossRefGoogle Scholar
  42. Shen, M., Piser T.M., Seybold, V.S. & Thayer, S.A. (1996). Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures.Journal of Neuroscience, 16, 4322–4334.PubMedGoogle Scholar
  43. Shen, M. & Thayer, S.A. (1998). Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity.Molecular Pharmacology, 54, 459–462.PubMedGoogle Scholar
  44. Simoneau, II, Hamza, M.S., Mata, H.P., Siegel, E.M., Vanderah, T.W., Porreca, F., Makryannis, A. & Malan, P. (2001). The cannabinoid agonist WIN 55,212-2 suppresses opioid-induced emesis in ferrets.Anesthesiology, 9, 882–886.CrossRefGoogle Scholar
  45. Sugiura, T., Kondo, S., Sukagawa, A., Nakane, S., Shinoda, A., Itoh, K., Yamashita, A. & Waku, K. (1995). 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain.Biochem. Biophys. Res. Commun, 215, 89–97.PubMedCrossRefGoogle Scholar
  46. Travers, J.B. & Norgren, J.B. (1986). Electromyographic analysis of the ingestion and rejection of sapid stimuli in the rat.Behavioral Neuroscience, 100, 544–555.PubMedCrossRefGoogle Scholar
  47. Van Sickle, M.D., Oland, L.D., Ho, W., Hillard, C.J., Mackie, K., Davison, J.S. & Sharkey, K.A. (2001). Cannabinoids inhibit emesis through CB1 receptors in the brainstem of the ferret.Gastroenterology, 121, 767–74.PubMedCrossRefGoogle Scholar
  48. Zalaquett, C., Parker, L.A. (1989). Further evidence that CTAs produced by lithium and amphetamine are qualitatively different.Learning and Motivation, 20, 413–427.CrossRefGoogle Scholar

Copyright information

© Springer 2003

Authors and Affiliations

  1. 1.Department of PsychologyWilfrid Laurier UniversityWaterloo
  2. 2.School of PharmacyHebrew University Medical FacultyJerusalemIsrael

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