BACKGROUND AND PURPOSEThe aim of this study was to compare the abilities of cannabidiolic acid methyl ester (HU-580) and cannabidiolic acid (CBDA) to enhance 5-HT 1A receptor activation in vitro and produce 5-HT 1A -mediated reductions in nausea and anxiety in vivo. EXPERIMENTAL APPROACHWe investigated the effects of HU-580 and CBDA on (i) activation by 8-hydroxy-2-(di-n-propylamino)tetralin of human 5-HT 1A receptors in CHO cell membranes, using [35 S]-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 RESULTSHU-580 and CBDA increased the E max 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 À1 i.p. and at 1 μg·kg À1 i.p., respectively, and (ii) anticipatory nausea at 0.01 and 0.1 μg·kg À1 , and at 0.1 μg·kg À1 i.p. respectively. At 0.01 μg·kg À1 , HU-580, but not CBDA, increased the time footshocked 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 À1 HU-580 were opposed by the 5-HT 1A antagonist, WAY100635 (0.1 mg·kg À1 i.p.). CONCLUSIONS AND IMPLICATIONSHU-580 is more potent than CBDA at enhancing 5-HT 1A 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-HT 1A receptor activation. Abbreviations

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