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

Background and purpose: To follow up in vitro evidence that Delta(9)-tetrahydrocannabivarin extracted from cannabis (e Delta(9)-THCV) is a CB1 receptor antagonist by establishing whether synthetic Delta(9)-tetrahydrocannabivarin (O-4394) and Delta(8)-tetrahydrocannabivarin (O-4395) behave as CB1 antagonists in vivo.

Experimental approach: O-4394 and O-4395 were compared with e Delta(9)-THCV as displacers of [H-3]-CP55940 from specific CB1 binding sites on mouse brain membranes and as antagonists of CP55940 in [S-35]GTP gamma S 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.) Delta(9)-tetrahydrocannabinol in mice was then investigated.

Key results: O-4394 and O-4395 exhibited similar potencies to e Delta(9)-THCV as displacers of [H-3]-CP55940 (K-i = 46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [S-35]GTP gamma S 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 Delta(9)-tetrahydrocannabinol-induced anti-nociception (tail-flick test) and hypothermia (rectal temperature). O-4395 but not O-4394 also antagonized Delta(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 e Delta(9)-THCV as CB1 receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Delta(9)-tetrahydrocannabinol in vivo.