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 H]‐CP55940 from specific CB 1 binding sites on mouse brain membranes and as antagonists of CP55940 in [ 35 S]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 H]‐CP55940 ( K i =46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [ 35 S]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 . British Journal of Pharmacology (2007) 150 , 586–594. doi: 10.1038/sj.bjp.0707124