Psychopharmacology

, Volume 231, Issue 16, pp 3207–3215

A comparison of cannabidiolic acid with other treatments for anticipatory nausea using a rat model of contextually elicited conditioned gaping

  • Erin M. Rock
  • Cheryl L. Limebeer
  • Roshan Navaratnam
  • Martin A. Sticht
  • Natasha Bonner
  • Kristin Engeland
  • Rachel Downey
  • Heather Morris
  • Meagan Jackson
  • Linda A. Parker
Original Investigation

Abstract

Rationale

The effectiveness of cannabidiolic acid (CBDA) was compared with other potential treatments for anticipatory nausea (AN), using a rat model of contextually elicited conditioned gaping reactions.

Objective

The potential of ondansetron (OND), Δ9-tetrahydrocannabinol (THC), chlordiazepoxide (CDP), CBDA, and co-administration of CBDA and tetrahydrocannabinolic acid (THCA) to reduce AN and modify locomotor activity was evaluated.

Materials and methods

Following four pairings of a novel context with lithium chloride (LiCl), the rats were given a test for AN. On the test trial, they received pretreatment injections of the following: vehicle, OND (0.1 or 1.0 mg/kg), THC (0.5 mg/kg), CBDA (0.0001, 0.001, 0.01, 0.1 mg/kg or 1.0 mg/kg), CDP (1, 5, or 10 mg/kg) or co-administration of subthreshold doses of CBDA (0.1 μg/kg), and THCA (5 μg/kg). Immediately following the AN test trial in all experiments, rats were given a 15 min locomotor activity test. Finally, the potential of CBDA (0.001, 0.01, 0.1, and 1 mg/kg) to attenuate conditioned freezing to a shock-paired tone was assessed.

Results

THC, CBDA, and CDP, but not OND, reduced contextually elicited gaping reactions. Co-administration of subthreshold doses of CBDA and THCA also suppressed AN, and this effect was blocked by pretreatment with either a cannabinoid receptor 1 (CB1) receptor antagonist or a 5-hydroxytryptamine 1A (5-HT1A) receptor antagonist. CDP (but not CBDA, THC or CBDA and THCA) also suppressed locomotor activity at effective doses. CBDA did not modify the expression of conditioned fear.

Conclusions

CBDA has therapeutic potential as a highly potent and selective treatment for AN without psychoactive or locomotor effects.

Keywords

Cannabidiolic acid Ondansetron Chlordiazepoxide Δ9-tetrahydrocannabinol Tetrahydrocannabinolic acid Conditioned fear Nausea Anticipatory nausea Activity 

References

  1. Bolognini D, Rock EM, Cluny NL, Cascio MG, Limebeer CL, Duncan M et al (2013) Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol 168:1456–1470PubMedCentralPubMedCrossRefGoogle Scholar
  2. Chaouloff F, Durand M, Mormede P (1997) Anxiety- and activity-related effects of diazepam and chlordiazepoxide in the rat light/dark and dark/light tests. Behav Brain Res 85:27–35PubMedCrossRefGoogle Scholar
  3. Cross-Mellor SK, Ossenkopp KP, Piomelli D, Parker LA (2007) Effects of the FAAH inhibitor, URB597, and anandamide on lithium-induced taste reactivity responses: a measure of nausea in the rat. Psychopharmacol (Berl) 190:135–143CrossRefGoogle Scholar
  4. Fegley D, Gaetani S, Duranti A, Tontini A, Mor M, Tarzia G et al (2005) Characterization of the fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB597): effects on anandamide and oleoylethanolamide deactivation. J Pharmacol Exp Ther 313:352–358PubMedCrossRefGoogle Scholar
  5. Gaoni Y, Mechoulam R (1964) Isolation, structure, and partial synthesis of an active constituent in hashish. J Am Chem Soc 86:1646–1647CrossRefGoogle Scholar
  6. Grill HJ, Norgren R (1978) The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically normal rats. Brain Res 143:263–279PubMedCrossRefGoogle Scholar
  7. Haller J, Hohmann J, Freund TF (2010) The effect of Echinacea preparations in three laboratory tests of anxiety: comparison with chlordiazepoxide. Phythother Res 24:1605–1613CrossRefGoogle Scholar
  8. Hsu ES (2010) A review of granisetron, 5-hydroxytryptamine3 receptor antagonists, and other antiemetics. Am J Ther 17:476–486PubMedCrossRefGoogle Scholar
  9. Kamen C, Tejani MA, Chandwani K, Janelsins M, Peoples AR, Roscoe JA et al (2014) Anticipatory nausea and vomiting due to chemotherapy. Eur J Pharmacol 722:172–179Google Scholar
  10. Kwiatkowska M, Parker LA, Burton P, Mechoulam R (2004) A comparative analysis of the potential of cannabinoids and ondansetron to suppress cisplatin-induced emesis in the Suncus murinus (house musk shrew). Psychopharmacol (Berl) 174:254–259CrossRefGoogle Scholar
  11. Lau AH, Rudd JA, Yew DT (2005) Action of ondansetron and CP-99,994 on cisplatin-induced emesis and locomotor activity in Suncus murinus (house musk shrew). Behav Pharmacol 16:605–612PubMedCrossRefGoogle Scholar
  12. Limebeer CL, Parker LA (1999) Delta-9-tetrahydrocannabinol interferes with the establishment and the expression of conditioned rejection reactions produced by cyclophosphamide: a rat model of nausea. Neuroreport 10:3769–3772PubMedCrossRefGoogle Scholar
  13. Limebeer CL, Parker LA (2000) The anti-emetic drug, ondansetron, interferes with lithium-induced conditioned rejection reactions, but not lithium-induced conditioned taste avoidance. J Exp Psych: Animal Behav Proc 26:371–384Google Scholar
  14. Limebeer CL, Parker LA (2003) The 5-HT1A agonist 8-OH-DPAT dose-dependently interferes with the establishment and the expression of lithium-induced conditioned rejection reactions in rats. Psychopharmacol (Berl) 166:120–126Google Scholar
  15. Limebeer CL, Hall G, Parker LA (2006) Exposure to a lithium-paired context elicits gaping in rats: a model of anticipatory nausea. Physiol Behav 88:398–403PubMedCrossRefGoogle Scholar
  16. Limebeer CL, Krohn JP, Cross-Mellor S, Litt DE, Ossenkopp KP, Parker LA (2008) Exposure to a context previously associated with nausea elicits conditioned gaping in rats: a model of anticipatory nausea. Behav Brain Res 187:33–40PubMedCrossRefGoogle Scholar
  17. Limebeer CL, Abdullah RA, Rock EM, Imhof E, Wang K, Lichtman AH, Parker LA (2014) Attenuation of anticipatory nausea in a rat model of contextually elicited conditioned gaping by enhancement of the endocannabinoid system. Psychopharmacol (Berl) 231:603–612CrossRefGoogle Scholar
  18. Malik IA, Khan WA, Qazilbash M, Ata E, Butt A, Khan MA (1995) Clinical efficacy of lorazepam in prophylaxis of anticipatory, acute, and delayed nausea and vomiting induced by high doses of cisplatin. A prospective randomized trial. Am J Clin Oncol 18:170–175PubMedCrossRefGoogle Scholar
  19. Maren S (1999) Neurotoxic basolateral amygdala lesions impair learning and memory but not the performance of conditional fear in rats. J Neurosci 19:8696–8703PubMedGoogle Scholar
  20. Mechoulam R, Gaoni Y (1965) Hashish. IV. The isolation and structure of cannabinolic cannabidiolic and cannabigerolic acids. Tetrahedron 21:1223–1229PubMedCrossRefGoogle Scholar
  21. Merlo Pich E, Samanin R (1989) A two-compartment exploratory model to study anxiolytic/anxiogenic effects of drugs in the rat. Pharmacol Res 21:595–602PubMedCrossRefGoogle Scholar
  22. Morrow GR, Hickok JT, Rosenthal SN (1995) Progress in reducing nausea and emesis. Comparisons of ondansetron (Zofran), granisetron (Kytril), and tropisetron (Navoban). Cancer 76:343–357PubMedCrossRefGoogle Scholar
  23. Morrow GR, Roscoe JA, Kirshner JJ, Hynes HE, Rosenbluth RJ (1998) Anticipatory nausea and vomiting in the era of 5-HT3 antiemetics. Support Care Cancer 6:244–247PubMedCrossRefGoogle Scholar
  24. Parker LA (1984) Behavioral conditioned responses across multiple conditioning/testing trials elicited by lithium- and amphetamine-paired flavors. Behav Neural Biol 41:190–199PubMedCrossRefGoogle Scholar
  25. Parker LA, Kemp SW (2001) Tetrahydrocannabinol (THC) interferes with conditioned retching in Suncus murinus: an animal model of anticipatory nausea and vomiting (ANV). Neuroreport 12:749–751PubMedCrossRefGoogle Scholar
  26. Parker LA, Kwiatkowska M, Burton P, Mechoulam R (2004) Effect of cannabinoids on lithium-induced vomiting in the Suncus murinus (house musk shrew). Psychopharmacol (Berl) 171:156–161CrossRefGoogle Scholar
  27. Parker LA, Kwiatkowska M, Mechoulam R (2006) Delta-9-tetrahydrocannabinol and cannabidiol, but not ondansetron, interfere with conditioned retching reactions elicited by a lithium-paired context in Suncus murinus: an animal model of anticipatory nausea and vomiting. Physiol Behav 87:66–71PubMedCrossRefGoogle Scholar
  28. Potter DJ, Clark P, Brown MB (2008) Potency of delta 9-THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology. J Forensic Sci 53:90–94PubMedCrossRefGoogle Scholar
  29. Ramos A, Pereira E, Martins GC, Wehrmeister TD, Izidio GS (2008) Integrating the open field, elevated plus maze and light/dark box to assess different types of emotional behaviors in one single trial. Behav Brain Res 193:277–288PubMedCrossRefGoogle Scholar
  30. Razavi D, Delvaux N, Farvacques C, De Brier F, Van Heer C, Kaufman L et al (1993) Prevention of adjustment disorders and anticipatory nausea secondary to adjuvant chemotherapy: a double-blind, placebo-controlled study assessing the usefulness of alprazolam. J Clin Oncol 11:1384–1390PubMedGoogle Scholar
  31. Rock EM, Parker LA (2013) Effect of low doses of cannabidiolic acid and ondansetron on LiCl-induced conditioned gaping (a model of nausea-induced behaviour) in rats. Br J Pharmacol 169:685–692PubMedCentralPubMedCrossRefGoogle Scholar
  32. Rock EM, Limebeer CL, Mechoulam R, Piomelli D, Parker LA (2008) The effect of cannabidiol and URB597 on conditioned gaping (a model of nausea) elicited by a lithium-paired context in the rat. Psychopharmacol (Berl) 196:389–395CrossRefGoogle Scholar
  33. Rock EM, Bolognini D, Limebeer C, Cascio M, Anavi-Goffer S, Fletcher P et al (2012) Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus. Br J Pharmacol 165:2620–2634PubMedCentralPubMedCrossRefGoogle Scholar
  34. Rock EM, Kopstick RL, Limebeer CL, Parker LA (2013) Tetrahydrocannabinolic acid reduces nausea-induced conditioned gaping in rats and vomiting in Suncus murinus. Br J Pharmacol 170:641–648PubMedCrossRefGoogle Scholar
  35. Rudd JA, Naylor RJ (1994) Effects of 5-HT3 receptor antagonists on models of acute and delayed emesis induced by cisplatin in the ferret. Neuropharmacology 33:1607–1608PubMedCrossRefGoogle Scholar
  36. Rudd JA, Naylor RJ (1996) An interaction of ondansetron and dexamethasone antagonizing cisplatin-induced acute and delayed emesis in the ferret. Br J Pharmacol 118:209–214PubMedCentralPubMedCrossRefGoogle Scholar
  37. Sam TS, Cheng JT, Johnston KD, Kan KK, Ngan MP, Rudd JA et al (2003) Action of 5-HT3 receptor antagonists and dexamethasone to modify cisplatin-induced emesis in Suncus murinus (house musk shrew). Eur J Pharmacol 472:135–145PubMedCrossRefGoogle Scholar
  38. Takeda S, Okajima S, Miyoshi H, Yoshida K, Okamoto Y, Okada T et al (2012) Cannabidiolic acid, a major cannabinoid in fiber-type cannabis, is an inhibitor of MDA-MB-231 breast cancer cell migration. Toxicol Lett 214:314–319PubMedCentralPubMedCrossRefGoogle Scholar
  39. Tuerke KJ, Winters BD, Parker LA (2012) Ondansetron interferes with unconditioned lying-on belly and acquisition of conditioned gaping induced by LiCl as models of nausea-induced behaviors in rats. Physiol Behav 105:856–860PubMedCrossRefGoogle Scholar
  40. Zuardi AW, Cosme RA, Graeff FG, Guimarães FS (1993) Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol 7:82–88PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Erin M. Rock
    • 1
  • Cheryl L. Limebeer
    • 1
  • Roshan Navaratnam
    • 1
  • Martin A. Sticht
    • 1
  • Natasha Bonner
    • 1
  • Kristin Engeland
    • 1
  • Rachel Downey
    • 1
  • Heather Morris
    • 1
  • Meagan Jackson
    • 1
  • Linda A. Parker
    • 1
  1. 1.Department of Psychology and Collaborative Neuroscience ProgramUniversity of GuelphGuelphCanada

Personalised recommendations