Cannabidiolic acid methyl ester, a stable synthetic analogue of cannabidiolic acid, can produce 5-HT1A receptor-mediated suppression of nausea and anxiety in rats

Roger G. Pertwee*, Erin M. Rock, Kelsey Guenther, Cheryl L. Limebeer, Lesley A. Stevenson, Christeene Haj, Reem Smoum, Linda A. Parker, Raphael Mechoulam

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Background and Purpose: The aim of this study was to compare the abilities of cannabidiolic acid methyl ester (HU-580) and cannabidiolic acid (CBDA) to enhance 5-HT1A receptor activation in vitro and produce 5-HT1A-mediated reductions in nausea and anxiety in vivo. Experimental Approach: We investigated the effects of HU-580 and CBDA on (i) activation by 8-hydroxy-2-(di-n-propylamino)tetralin of human 5-HT1A receptors in CHO cell membranes, using [35S]-GTPγS binding assays, (ii) gaping by rats in acute and anticipatory nausea models, and (iii) stress-induced anxiety-like behaviour, as indicated by exit time from the light compartment of a light–dark box of rats subjected 24 h earlier to six tone-paired foot shocks. Key Results: HU-580 and CBDA increased the Emax of 8-hydroxy-2-(di-n-propylamino) tetralin in vitro at 0.01–10 and 0.1–10 nM, respectively, and reduced signs of (i) acute nausea at 0.1 and 1 μg·kg−1 i.p. and at 1 μg·kg−1 i.p., respectively, and (ii) anticipatory nausea at 0.01 and 0.1 μg·kg−1, and at 0.1 μg·kg−1 i.p. respectively. At 0.01 μg·kg−1, HU-580, but not CBDA, increased the time foot-shocked rats spent in the light compartment of a light–dark box. The anti-nausea and anti-anxiety effects of 0.01 or 0.1 μg·kg−1 HU-580 were opposed by the 5-HT1A antagonist, WAY100635 (0.1 mg·kg−1 i.p.). Conclusions and Implications: HU-580 is more potent than CBDA at enhancing 5-HT1A receptor activation, and inhibiting signs of acute and anticipatory nausea, and anxiety. Consequently, HU-580 is a potential medicine for treating some nausea and anxiety disorders and possibly other disorders ameliorated by enhancement of 5-HT1A receptor activation.

Original languageAmerican English
Pages (from-to)100-112
Number of pages13
JournalBritish Journal of Pharmacology
Volume175
Issue number1
DOIs
StatePublished - Jan 2018

Bibliographical note

Funding Information:
The in vivo research described in this paper was supported by a grant from Natural Sciences and Engineering Council of Canada to L.A.P. The authors would like to thank Dr. Keith Parker for supplying CHO cells stably transfected with human 5-HT1Areceptors.

Publisher Copyright:
© 2017 The British Pharmacological Society

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