Effects of Δ 9 ‐tetrahydrocannabivarin on [ 35 S]GTPγS binding in mouse brain cerebellum and piriform cortex membranes

Background and purpose: We have recently shown that the phytocannabinoid Δ 9 ‐tetrahydrocannabivarin (Δ 9 ‐THCV) and the CB 1 receptor antagonist AM251 increase inhibitory neurotransmission in mouse cerebellum and also exhibit anticonvulsant activity in a rat piriform cortical (PC) model of epilepsy. Possible mechanisms underlying cannabinoid actions in the CNS include CB 1 receptor antagonism (by displacing endocannabinergic tone) or inverse agonism at constitutively active CB 1 receptors. Here, we investigate the mode of cannabinoid action in [ 35 S]GTPγS binding assays. Experimental approach: Effects of Δ 9 ‐THCV and AM251 were tested either alone or against WIN55,212‐2‐induced increases in [ 35 S]GTPγS binding in mouse cerebellar and PC membranes. Effects on non‐CB receptor expressing CHO‐D 2 cell membranes were also investigated. Key results: Δ 9 ‐THCV and AM251 both acted as potent antagonists of WIN55,212‐2‐induced increases in [ 35 S]GTPγS binding in cerebellar and PC membranes (Δ 9 ‐THCV: pA 2 =7.62 and 7.44 respectively; AM251: pA 2 =9.93 and 9.88 respectively). At micromolar concentrations, Δ 9 ‐THCV or AM251 alone caused significant decreases in [ 35 S]GTPγS binding; Δ 9 ‐THCV caused larger decreases than AM251. When applied alone in CHO‐D 2 membranes, Δ 9 ‐THCV and AM251 also caused concentration‐related decreases in G protein activity. Conclusions and implications: Δ 9 ‐THCV and AM251 act as CB 1 receptors antagonists in the cerebellum and PC, with AM251 being more potent than Δ 9 ‐THCV in both brain regions. Individually, Δ 9 ‐THCV or AM251 exhibited similar potency at CB 1 receptors in the cerebellum and the PC. At micromolar concentrations, Δ 9 ‐THCV and AM251 caused a non‐CB receptor‐mediated depression of basal [ 35 S]GTPγS binding. British Journal of Pharmacology (2008) 154 , 1349–1358; doi: 10.1038/bjp.2008.190 ; published online 19 May 2008