The psychoactive plant cannabinoid, Δ 9- tetrahydrocannabinol, is antagonized by Δ 8- and Δ 9-tetrahydrocannabivarin in mice in vivo

Background and purpose: To follow up in vitro evidence that Δ ⁹-tetrahydrocannabivarin extracted from cannabis (eΔ ⁹-THCV) is a CB ₁ receptor antagonist by establishing whether synthetic Δ ⁹-tetrahydrocannabivarin (O-4394) and Δ ⁸-tetrahydrocannabivarin (O-4395) behave as CB ₁ antagonists in vivo. Experimental approach: O-4394 and O-4395 were compared with eΔ ⁹-THCV as displacers of [ ³]-CP55940 from specific CB ₁ binding sites on mouse brain membranes and as antagonists of CP55940 in [ ³⁵S]GTPγS binding assays performed with mouse brain membranes and of R-(+)-WIN55212 in mouse isolated vasa deferentia. Their ability to antagonize in vivo effects of 3 or 10 mg kg ^-1 (i.v.) Δ ⁹-tetrahydrocannabinol in mice was then investigated. Key results: O-4394 and O-4395 exhibited similar potencies to eΔ ⁹-THCV as displacers of [ ³]-CP55940 (K _i=46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [ ³⁵S]GTPγS binding assay (apparent K _B=82.1 and 125.9 nM, respectively) and R-(+)-WIN55212 in the vas deferens (apparent K _B=4.8 and 3.9 nM respectively). At i.v. doses of 0.1, 0.3, 1.0 and/or 3 mg kg ^-1 O-4394 and O-4395 attenuated Δ ⁹- tetrahydrocannabinol-induced anti-nociception (tail-flick test) and hypothermia (rectal temperature). O-4395 but not O-4394 also antagonized Δ ⁹-tetrahydrocannabinol-induced ring immobility. By themselves, O-4395 and O-4394 induced ring immobility at 3 or 10 mg kg ^-1 (i.v.) and antinociception at doses above 10 mg kg ^-1 (i.v.). O-4395 also induced hypothermia at 3 mg kg ^-1 (i.v.) and above. Conclusions and implications: O-4394 and O-4395 exhibit similar in vitro potencies to eΔ ⁹-THCV as CB ₁ receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Δ ⁹- tetrahydrocannabinol in vivo.