The psychoactive plant cannabinoid, Δ9‐tetrahydrocannabinol, is antagonized by Δ8‐ and Δ9‐tetrahydrocannabivarin in mice in vivo

Abstract

Background and purpose:To follow up in vitro evidence that Δ9‐tetrahydrocannabivarin extracted from cannabis (eΔ9‐THCV) is a CB1 receptor antagonist by establishing whether synthetic Δ9‐tetrahydrocannabivarin (O‐4394) and Δ8‐tetrahydrocannabivarin (O‐4395) behave as CB1 antagonists in vivo.Experimental approach:O‐4394 and O‐4395 were compared with eΔ9‐THCV as displacers of [3H]‐CP55940 from specific CB1 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.) Δ9‐tetrahydrocannabinol in mice was then investigated.Key results:O‐4394 and O‐4395 exhibited similar potencies to eΔ9‐THCV as displacers of [3H]‐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 Δ9‐tetrahydrocannabinol‐induced anti‐nociception (tail‐flick test) and hypothermia (rectal temperature). O‐4395 but not O‐4394 also antagonized Δ9‐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 eΔ9‐THCV as CB1 receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Δ9‐tetrahydrocannabinol in vivo.British Journal of Pharmacology (2007) 150, 586–594. doi:10.1038/sj.bjp.0707124