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. 2013 Jun;169(3):685-92. doi: 10.1111/bph.12162.


Background and purpose: To determine the minimally effective dose of cannabidiolic acid (CBDA) that effectively reduces lithium chloride (LiCl)-induced conditioned gaping reactions (nausea-induced behaviour) in rats and to determine if these low systemic doses of CBDA (5-0.1 μg·kg⁻¹) relative to those of CBD could potentiate the anti-nausea effects of the classic 5-hydroxytryptamine 3 (5-HT₃) receptor antagonist, ondansetron (OND).

Experimental approach: We investigated the efficacy of low doses of CBDA to suppress acute nausea, assessed by the establishment of conditioned gaping to a LiCl-paired flavour in rats. The potential of threshold and subthreshold doses of CBDA to enhance the reduction of nausea-induced conditioned gaping by OND were then determined.

Key results: CBDA (at doses as low as 0.5 μg·kg⁻¹) suppressed nausea-induced conditioned gaping to a flavour. A low dose of OND (1.0 μg·kg⁻¹) alone reduced nausea-induced conditioned gaping, but when it was combined with a subthreshold dose of CBDA (0.1 μg·kg⁻¹) there was an enhancement in the suppression of LiCl-induced conditioned gaping.

Conclusions and implications: CBDA potently reduced conditioned gaping in rats, even at low doses and enhanced the anti-nausea effect of a low dose of OND. These findings suggest that combining low doses of CBDA and OND will more effectively treat acute nausea in chemotherapy patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiemetics / administration & dosage*
  • Antiemetics / antagonists & inhibitors
  • Antiemetics / therapeutic use
  • Antineoplastic Agents / adverse effects*
  • Behavior, Animal / drug effects
  • Cannabinoids / administration & dosage*
  • Cannabinoids / antagonists & inhibitors
  • Cannabinoids / therapeutic use
  • Conditioning, Psychological / drug effects
  • Disease Models, Animal*
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Drug Therapy, Combination
  • Injections, Intraperitoneal
  • Lithium Chloride
  • Male
  • Nausea / chemically induced
  • Nausea / prevention & control*
  • Ondansetron / administration & dosage*
  • Ondansetron / therapeutic use
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / chemistry
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Serotonin 5-HT1 Receptor Antagonists / pharmacology
  • Serotonin 5-HT3 Receptor Antagonists / administration & dosage*
  • Serotonin 5-HT3 Receptor Antagonists / therapeutic use
  • Taste


  • Antiemetics
  • Antineoplastic Agents
  • Cannabinoids
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin 5-HT3 Receptor Antagonists
  • Receptor, Serotonin, 5-HT1A
  • Ondansetron
  • cannabidiolic acid
  • Lithium Chloride