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

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.