, Volume 166, Issue 2, pp 156–162 | Cite as

Effects of cannabinoids on lithium-induced conditioned rejection reactions in a rat model of nausea

  • Linda A. ParkerEmail author
  • Raphael Mechoulam
  • Coralynn Schlievert
  • Laura Abbott
  • Melissa L. Fudge
  • Page Burton
Original Investigation



Marijuana has been reported to suppress nausea produced by chemotherapy treatment in human cancer patients. Although there is abundant evidence that cannabinoid agonists attenuate vomiting in emetic species, there has been little experimental evidence of their anti-nausea potential. Considerable evidence suggests that conditioned rejection reactions in rats reflect nausea. The present experiments evaluated the potential of low doses of the cannabinoid agonists, Δ-9-tetrahydrocannabinol (THC; 0.5 mg/kg, i.p.), and HU-210 (0.001 mg/kg and 0.01 mg/kg, i.p.), and the CB1 antagonist SR-141716A in modulating the establishment and the expression of lithium-induced conditioned rejection reactions in rats.


To evaluate the effect of cannabinoids on conditioned rejection reactions, a rat model of nausea.


In experiments 1 and 2, respectively, rats were injected with cannabinoid agonists, THC (0.5 mg/kg, i.p.) and HU-210 (0.001, 0.005 or 0.01 mg/kg), 30 min prior to exposure to 0.1% saccharin solution by intraoral infusion. Immediately following saccharin exposure, they were injected with 20 ml/kg 0.15 M lithium chloride or saline. On each of two test trials, the rats were injected with the cannabinoid or vehicle 30 min prior to exposure to saccharin. In experiment 3, rats were injected with the CB1 antagonist, SR-141716A (2.5 mg/kg) or a combination of SR-141716A and HU-210 (0.01 mg/kg) 30 min prior to an infusion of saccharin followed by injection of lithium or saline. They were given a single drug-free test trial. Experiment 4 replicated and extended the findings of experiment 3.


Δ-9-THC and HU-210 interfered with the establishment and the expression of lithium-induced conditioned rejection reactions. The suppressive effect of HU-210 on rejection reactions was reversed by pretreatment with SR-141716A. Administration of SR-141716A prior to conditioning potentiated lithium-induced conditioned rejection reactions.


These results indicate that the establishment and the expression of lithium-induced conditioned rejection reactions are suppressed by pretreatment with cannabinoid agents. These effects appear to be mediated by their action on the CB1 receptor, because they are reversed by pretreatment with SR-141716A. Finally, our results suggest that endogenous cannabinoids play a role in modulation of nausea, because the antagonist potentiated lithium-induced nausea.


Nausea Taste reactivity Cannabinoids Marijuana Taste aversion Learning Rat 



The research in Canada was supported by a research grant from the Canadian Institutes of Health Research to Linda Parker. The research in Israel was supported by the Israel Science Foundation. We would like to thank Marion Corrick for excellent care of the animals throughout these experiments. Reprint requests to Linda Parker.


  1. Blackshaw LA, Grundy D (1993) Effects of 5-hydroxytryptamine on discharge of vagal mucosal afferent fibres from the upper gastrointestinal tract of the ferret. J Autonom Nerv Sys 45:41–50Google Scholar
  2. Darmani NA (2001a) Delta-9-tetrahydrocannabinol and synthetic cannabinoids prevent emesis produced by the cannabinoid CB1 receptor antagonist/inverse agonist SR-41716A. Neuropsychopharmacology 24:198–203Google Scholar
  3. Darmani NA (2001b) Delta-9-tetrahydrocannabinol differentially suppresses cisplatin-induced emesis and indices of motor function via cannabinoid CB1 receptors in the least shrew. Pharmacol Biochem Behav 69:239–249CrossRefPubMedGoogle Scholar
  4. Darmani NA (2001c) The cannabinoid CB1 receptor antagonist SR 141716A reverses the antiemetic and motor depressant actions of WIN 55,212–2. Eur J Pharmacol 430:49–58CrossRefPubMedGoogle Scholar
  5. Darmani NA (2002) The potent emetogenic effects of the endocannabinoid, 2-AG (2-arachidonoylglycerol) are blocked by delta(9)-tetrahydrocannabinol and other cannabinoids. J Pharmacol Exp Ther 300:34–42PubMedGoogle Scholar
  6. Davis CJ, Harding RK, Leslie RA, Andrews PLR (1986) The organisation of vomiting as a protective reflex. In: Davis CJ, Lake-Bakaar GV, Grahame-Smith DG (eds) Nausea and vomiting: mechanisms and treatment. Springer, Berlin Heidelberg New York, pp 65–75Google Scholar
  7. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, 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 258:1946–1949PubMedGoogle Scholar
  8. Feigenbaum JJ, Richmond SA, Weissman Y, Mechoulam R (1989) Inhibition of cisplatin-induced emesis in the pigeon by a non-psychotropic synthetic cannabinoid. Eur J Pharmacol 4:159–165CrossRefGoogle Scholar
  9. Ferrari F, Ottani A, Giuliani D (1999) Cannabimimetic activity in rats and pigeons of HU-210, a potent antiemetic drug. Pharmacol Biochem Behav 62:75–80CrossRefPubMedGoogle Scholar
  10. Grill HC, Norgren R (1978) The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically normal rats. Brain Res 143:263–279PubMedGoogle Scholar
  11. Hampson AJ, Grimaldi M, Axelrod J (1998) Cannabidiol and delta-9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95:8268–8273CrossRefPubMedGoogle Scholar
  12. Hanus L, Abu-Lafi S, Fride E, Breuer A, Vogel Z, Shalev DE, Kustanovick I, Mechoulam R (2001) 2-Arachidonoyl glycerol ether, endogenous agonist of the cannabinoid CB1 receptor. Proc Natl Acad Sci USA 98:3662–3665CrossRefPubMedGoogle Scholar
  13. Jin KL, Mao XO, Goldsmith PC, Greenberg DA (2000) CB1 cannabinoid receptor induction in experimental stroke. Ann Neurol 48:257–261CrossRefPubMedGoogle Scholar
  14. Limebeer CL, Parker LA (1999) Delta-9-tetrahydrocannabinol interferes with the establishment and the expression of conditioned disgust reactions produced by cyclophoshamide: a rat model of nausea. Neuroreport 10:3769–3772PubMedGoogle Scholar
  15. Limebeer CL, Parker LA (2000) Ondansetron interferes with the establishment and the expression of conditioned disgust reactions: a rat model of nausea. J Exp Psychol Anim Behav Process 26:371–384CrossRefPubMedGoogle Scholar
  16. Lowe S (1946) Studies on the pharmacology and acute toxicity of compounds with marihuana activity. J Pharmacol Exp Ther 88:154–161Google Scholar
  17. McCarthy LE, Borison HL (1984) Cisplatin-induced vomiting eliminated by ablation of the area postrema in cats. Cancer Treat Rep 68:401–404PubMedGoogle Scholar
  18. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, Pertwee RG, Griffin G, Bayewitch M, Marg J, Vogel Z (1995) Identification of an endogenous 2-monoglyceride, present in canine gut that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90PubMedGoogle Scholar
  19. Parker LA (1982) Nonconsummatory and consummatory behavioral CRs elicited by lithium- and amphetamine-paired flavors. Learn Motiv 13:281–303Google Scholar
  20. Parker LA (1995) Rewarding drugs produce taste avoidance, but not taste aversion. Neurosci Biobehav Rev 19:143–151PubMedGoogle Scholar
  21. Parker LA (1998) Emetic drugs produce conditioned rejection reactions in the taste reactivity test. J Psychophysiol 12:3–13Google Scholar
  22. Parker LA, McLeod KB (1991) Chin rub CRs may reflect conditioned sickness elicited by a lithium-paired sucrose solution. Pharmacol Biochem Behav 40:983–986PubMedGoogle Scholar
  23. Parker LA, Mechoulam R, Schlievert C (2002) Cannabidiol, a non-psychoactive component of cannabis and its dimethylheptyl homolog suppress nausea in an experimental model with rats. Neuroreport 13:567–570PubMedGoogle Scholar
  24. Pelchat ML, Grill HJ, Rozin P, Jacobs J (1983) Quality of acquired responses to tastes by Rattus norvegicus depends on type of associated discomfort. J Comp Psychol 97:140–153CrossRefPubMedGoogle Scholar
  25. Rudd JA, Ngan MP, Wai MK (1998) 5-HT3 receptors are not involved in conditioned taste aversions induced by 5-hydroxytryptamine, ipecacuanha or cisplatin. Eur J Pharmacol 352:143–149CrossRefPubMedGoogle Scholar
  26. Sallen SE, Zinberg NE, Frei III E (1975) Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med 293:795–798PubMedGoogle Scholar
  27. Schmid PC, Krebsbach RJ, Perry SR, Dettmer TM, Maasson JL, Schmid HH (1995) Occurrence and postmortem generation of anandamide and other long-chain N-acylethanolamines in mammalian brain. FEBS Lett 375:117–120CrossRefPubMedGoogle Scholar
  28. Shen M, Thayer SA (1998) Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Mol Pharmacol 54:459–462PubMedGoogle Scholar
  29. Shen M, Piser TM, Seybold VS, Thayer SA (1996) Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J Neurosci 16:4322–4334PubMedGoogle Scholar
  30. Simoneau II, Hamza MS, Mata HP, Siegel EM, Vanderah TW, Porreca F, Makryannis A, Malan P (2001) The cannabinoid agonist WIN 55,212–2 suppresses opioid-induced emesis in ferrets. Anesthesiology 94:882–886PubMedGoogle Scholar
  31. 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 215:89–97Google Scholar
  32. Van Sickle MD, Oland LD, HO W, Hillard CJ, Mackie K, Davison JS, Sharkey KA (2001) Cannabinoids inhibit emesis through CB1 receptors in the brainstem of the ferret. Gastroenterology 121:767–774PubMedGoogle Scholar
  33. Zalaquett C, Parker LA (1989) Further evidence that CTAs produced by lithium and amphetamine are qualitatively different. Learn Motiv 20:413–427Google Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Linda A. Parker
    • 1
    Email author
  • Raphael Mechoulam
    • 2
  • Coralynn Schlievert
    • 1
  • Laura Abbott
    • 1
  • Melissa L. Fudge
    • 1
  • Page Burton
    • 1
  1. 1.Department of PsychologyWilfrid Laurier UniversityWaterlooCanada N2L 3C5
  2. 2.Department of Medicinal Chemistry and Natural ProductsThe Hebrew University of JerusalemJerusalemIsrael

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