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Effects of Delta(9)-tetrahydrocannabivarin on [(35)S]GTPgammaS binding in mouse brain cerebellum and piriform cortex membranes.
Br J Pharmacol. 2008 May 19;
Authors: Dennis I, Whalley BJ, Stephens GJ
Background and purpose:We have recently shown that the phytocannabinoid Delta(9)-tetrahydrocannabivarin (Delta(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]GTPgammaS binding assays.Experimental approach:Effects of Delta(9)-THCV and AM251 were tested either alone or against WIN55,212-2-induced increases in [(35)S]GTPgammaS binding in mouse cerebellar and PC membranes. Effects on non-CB receptor expressing CHO-D(2) cell membranes were also investigated.Key results:Delta(9)-THCV and AM251 both acted as potent antagonists of WIN55,212-2-induced increases in [(35)S]GTPgammaS binding in cerebellar and PC membranes (Delta(9)-THCV: pA(2)=7.62 and 7.44 respectively; AM251: pA(2)=9.93 and 9.88 respectively). At micromolar concentrations, Delta(9)-THCV or AM251 alone caused significant decreases in [(35)S]GTPgammaS binding; Delta(9)-THCV caused larger decreases than AM251. When applied alone in CHO-D(2) membranes, Delta(9)-THCV and AM251 also caused concentration-related decreases in G protein activity.Conclusions and implications:Delta(9)-THCV and AM251 act as CB(1) receptors antagonists in the cerebellum and PC, with AM251 being more potent than Delta(9)-THCV in both brain regions. Individually, Delta(9)-THCV or AM251 exhibited similar potency at CB(1) receptors in the cerebellum and the PC. At micromolar concentrations, Delta(9)-THCV and AM251 caused a non-CB receptor-mediated depression of basal [(35)S]GTPgammaS binding.British Journal of Pharmacology advance online publication, 19 May 2008; doi:10.1038/bjp.2008.190.
PMID: 18493244 [PubMed - as supplied by publisher]