CONCURRENT STIMULATION OF CANNABINOID CB1 AND DOPAMINE D2 RECEPTORS AUGMENTS CAMP ACCUMULATION IN STRIATAL NEURONS - EVIDENCE FOR A G(S) LINKAGE TO THE CB1 RECEPTOR

Cannabinoids act at the CB1 receptor to inhibit adenylate cyclase acti vity via a pertussis toxin-sensitive G-protein. Within the striatum, C B1 receptors have been shown to be localized on the same neurons as G( i)-coupled dopamine D2 receptors. In this study we have examined the i nteractions of CB1 and D2 receptors on adenylate cyclase. In striatal neurons in primary culture, both the CB1 receptor agonist [3-(1,1 -dim ethylheptyl)-11 -hydroxy-Delta(8)tetrahydrocannabinol] (HU210) and the D2 receptor agonist quinpirole inhibited forskolin-stimulated cAMP ac cumulation when applied separately. In contrast, HU210 and quinpirole in combination augmented cAMP accumulation. This augmentation was bloc ked by the CB1 receptor antagonist SR141716A or the D2 antagonist sulp ride. Pertussis toxin treatment of striatal neurons prevented the inhi bition of cAMP accumulation by D2 receptors but unmasked a cannabinoid receptor-mediated stimulatory effect on cAMP accumulation. The cannab inoid receptor-stimulated accumulation of cAMP was blocked in a concen tration-dependent manner by SR141716A, suggesting that the response wa s regulated through the CB1 receptor. Similar augmentation of cAMP acc umulation after pertussis toxin treatment was observed in Chinese hams ter ovary (CHO) cells transfected with, and stably expressing, the CB1 receptor. This stimulation of cAMP was not Ca2+-sensitive and was una ffected by a range of protein kinase inhibitors. Treatment of the pert ussis toxin-treated cells with cholera toxin before CB1 receptor activ ation amplified the stimulatory pathway, suggesting that this response was mediated through a G(s)-type G-protein. Stimulation of cAMP accum ulation was not observed after pertussis toxin treatment of CHO cells expressing the human CB2 receptor, suggesting that this novel signalin g pathway is unique to the cannabinoid CB1 receptor.