Effects of Delta super(9)-tetrahydrocannabivarin on [ super(35)S]GTP gamma S binding in mouse brain cerebellum and piriform cortex membranes

• Published in: British journal of pharmacology 2008-07, Vol.154 (6), p.1349-1358
• Main Authors: Dennis, I, Whalley, B J, Stephens, G J
• Format: Article
• Language: English
• ISSN: 0007-1188
• DOI: 10.1038/bjp.2008.190

Background and purpose: We have recently shown that the phytocannabinoid Delta super(9)-tetrahydrocannabivarin ( Delta super(9)-THCV) and the CB sub(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 sub(1) receptor antagonism (by displacing endocannabinergic tone) or inverse agonism at constitutiveiy active CB sub(1) receptors. Here, we investigate the mode of cannabinoid action in [ super(3S)S]GTPyS binding assays. Experimental approach: Effects of Delta super(9)-THCV and AM251 were tested either alone or against WIN55,212-2-induced increases in [ super(35)S]GTP gamma S binding in mouse cerebellar and PC membranes. Effects on non-CB receptor expressing CHO-D sub(2) cell membranes were also investigated. Key results: Delta super(9)-THCV and AM251 both acted as potent antagonists of WIN55,212-2-induced increases in [ super(35)S]GTP gamma S binding in cerebellar and PC membranes ( Delta super(9)-THCV: pA sub(2) = 7.62 and 7.44 respectively; AM251: pA sub(2) = 9.93 and 9.88 respectively). At micromolar concentrations, Delta super(9)-THCV or AM251 alone caused significant decreases in [ super(35)S]GTP gamma S binding; Delta super(9)-THCV caused larger decreases than AM251. When applied alone in CHO-D sub(2) membranes, Delta super(9)-THCV and AM251 also caused concentration-related decreases in G protein activity. Conclusions and implications: Delta super(9)-THCV and AM251 act as CB sub(1) receptors antagonists in the cerebellum and PC, with AM251 being more potent than Delta super(9)-THCV in both brain regions. Individually, Delta super(9)-THCV or AM251 exhibited similar potency at CB sub(1) receptors in the cerebellum and the PC. At micromolar concentrations, Delta super(9)-THCV and AM251 caused a non-CB receptor-mediated depression of basal [ super(35)S]GTP gamma S binding.