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:

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 to produce 5-HT_1A -mediated reductions of 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-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 RESULTS:

HU-580 and CBDA increased the E_max of 8-hydroxy-2-(di-n-propylamino)tetralin in vitro at 0.01-10 nM 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 i.p. and at 0.1 μg·kg^-1 i.p., respectively. At 0.01 μg·kg^-1 i.p., HU-580, but not CBDA, increased time spent in the light compartment of a light-dark box by foot-shocked rats. The anti-nausea and anti-anxiety effects of 0.01 or 0.1 μg·kg^-1 HU-580 were opposed by the 5-HT_1A antagonist, WAY100635 (0.1 mg·kg^-1 i.p.).

CONCLUSIONS AND IMPLICATIONS:

HU-580 is more potent than CBDA at enhancing 5-HT_1A receptor activation, and inducing inhibition of signs of acute and anticipatory nausea, and of anxiety. Consequently, HU-580 is a potential medicine for treating some nausea and anxiety disorders, and possibly also other disorders ameliorated by enhancement of 5-HT_1A receptor activation.

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