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, 169 (3), 685-92

Effect of Low Doses of Cannabidiolic Acid and Ondansetron on LiCl-induced Conditioned Gaping (A Model of Nausea-Induced Behaviour) in Rats

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Effect of Low Doses of Cannabidiolic Acid and Ondansetron on LiCl-induced Conditioned Gaping (A Model of Nausea-Induced Behaviour) in Rats

E M Rock et al. Br J Pharmacol.

Abstract

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.

Figures

Figure 1
Figure 1
Effect of CBDA (0.1, 0.5, 1 and 5 μg·kg−1) or VEH (i.p.) administered 45 min prior to LiCl. The number of conditioned gaping responses was measured during the drug-free test trial. Each bar represents the mean ± SEM (n = 8–12). The asterisks indicate a significant difference from the VEH-treated control animals (**P < 0.03, ***P < 0.001).
Figure 2
Figure 2
Effect of CBDA (0.1, 0.5, 1 and 5 μg·kg−1) or VEH (i.p.) administered 45 min prior to LiCl. The number of tongue protrusions was measured during the conditioning trial. Each bar represents the mean ± SEM (n = 8–12).
Figure 3
Figure 3
Effect of CBDA (0.1, 0.5, 1, and 5 μg·kg−1) or VEH (i.p.) administered 45 min prior to LiCl. The cumulative amount of saccharin solution consumed (mL ± SEM) during a one-bottle consumption test was measured at 30, 120 and 360 min after introduction of the bottle to fluid-restricted rats.
Figure 4
Figure 4
Effect of CBDA (0.5 μg kg−1) or VEH (i.p.) administered 15 min prior to OND (10 μg·kg−1 i.p.) or SAL (i.p.) in LiCl-treated rats. The number of conditioned gaping responses was measured during the test trial. Each bar represents the mean number of conditioned gaping responses ± SEM (n = 8). The asterisks indicate a significant difference from the VEH-treated control animals (**P < 0.003, ***P < 0.001).
Figure 5
Figure 5
Effect of CBDA (0.1 μg·kg−1) or VEH (i.p.) administered 15 min prior to OND (1 μg·kg−1) or SAL (i.p.) in LiCl-treated rats. The number of conditioned gaping responses was measured during the test trial. In Part A, each bar represents the mean number of conditioned gaping responses ± SEM (n = 6–8). In Part B, the number of tongue protrusions was measured during the conditioning trial. Each bar represents the mean ± SEM. In part C, the cumulative amount of saccharin solution consumed (mL ± SEM) during a one-bottle consumption test was measured at 30, 120 and 360 min after introduction of the bottle to fluid-restricted rats. The asterisks indicate a significant difference from the VEH-treated control animals (*P < 0.05, ***P < 0.001). As well, ## indicates that the group given the combination of 0.1 CBDA-1 OND showed less gaping than Group VEH-OND (P < 0.01).

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