Signal transduction interactions between CB 1 cannabinoid and dopamine receptors in the rat and monkey striatum

Abstract

Signal transduction interactions between the CB 1 cannabinoid and D 1 and D 2 dopamine receptor systems were studied in rat (Sprague Dawley) and monkey (Macaca fascilaris) striatal membranes. The D 2 agonist quinelorane inhibited forskolin (10 μM)-stimulated adenylyl cyclase in a dose-dependent manner (26% and 20% maximal inhibition; EC 50=2 and 0.5 μM, in rats and monkeys, respectively) and maximal inhibition was completely blocked by the D 2 antagonist sulpiride (10 μM). The CB 1 agonist desacetyllevonantradol inhibited forskolin-stimulated adenylyl cyclase (18% and 36% maximal inhibition; EC 50=160 and 73 nM, in rats and monkeys, respectively) and the CB 1 antagonist SR141716A (10 μM) completely blocked the maximal inhibition. Combined addition of >EC 90 concentrations of quinelorane (10, 30 μM) and desacetyllevonantradol (1 μM) resulted in no greater inhibition than that produced by either drug alone, indicative of signal transduction convergence between the D 2 and CB 1 receptor systems. The D 1 agonist 6-Br-APB (3-allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin) produced a dose-dependent stimulation of adenylyl cyclase (45% and 26% stimulation; EC 50=24 and 32 nM, in rat and monkey, respectively), and maximal stimulation was completely blocked by the D 1 antagonist SCH23390 (1 μM). D 1 agonist-stimulated activity could be inhibited to basal levels with desacetyllevonantradol (1 μM), indicative of D 1 and CB 1 signal transduction convergence. The data suggest that CB 1 receptors are co-localized with D 1 or D 2 receptors on the same population of striatal membranes and can interact at the level of G-protein/adenylyl cyclase signal transduction. Similar results obtained with both rat and monkey membranes indicate that striatal dopamine and cannabinoid interactions are conserved for these two species.