Characterization of cannabinoid agonists and apparent pA2 analysis of cannabinoid antagonists in rhesus monkeys discriminating Δ9- tetrahydrocannabinol

Cannabinoid CB1 receptors are hypothesized to mediate the discriminative stimulus effects of cannabinoids. This study characterized a Delta(9)-tetrahydrocannabinol (Delta(9)-THC; 0.1 mg/ kg i. v.) discriminative stimulus and examined antagonism of cannabinoid agonists in rhesus monkeys. High levels of responding on the Delta(9)-THC lever were produced by cannabinoid agonists with the following rank order potency: CP 55940 [(-)-cis-3-[ 2-hydroxy-4(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol] > Delta(9)-THC = WIN 55212-2 [(+)-[ 2,3-dihydro-5-methyl-3[(4-morpholinyl) methyl] pyrrolo[ 1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate salt] > arachidonyl-cyclopropylamide = (R)-methanandamide. A CB2-selective agonist, AM 1241 [(R)-3-(2-iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole], and noncannabinoids (cocaine, ketamine, midazolam, and morphine) did not produce high levels of Delta(9)-THC lever responding. The CB 1-selective antagonist SR 141716A [ N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)4-methyl-1H-pyrazole-3-carboxamide] surmountably antagonized the discriminative stimulus effects of Delta(9)-THC and CP 55940, and Schild analysis was consistent with a simple, competitive interaction (apparent pA(2) values were 6.1 and 6.7, respectively). SR 141716A surmountably antagonized WIN 55212-2; however, larger doses disrupted responding, precluding Schild analysis. The CB 1-selective antagonist AM 251 surmountably antagonized Delta(9)-THC, CP 55940, and WIN 55212-2, and Schild analysis was consistent with a simple, competitive interaction (apparent pA(2) values were 6.3, 6.1, and 6.2, respectively). The CB 2-selective antagonist SR 144528 [ N-[(1S)-endo-1,3,3-trimethylbicyclo(2.2.1) heptan-2-yl] 5-(4-chloro-3-methyl-phenyl)1-(4-methylbenzyl) pyrazole-3-carboxamide] did not modify the Delta(9)-THC discriminative stimulus. These results demonstrate that the discriminative stimulus effects of Delta(9)-THC are selective for cannabinoid activity, and the results of Schild analysis suggest that the same receptors mediate the discriminative stimulus effects of Delta(9)-THC, CP 55940, and WIN 55212-2. CB2 receptors do not seem to mediate the discriminative stimulus effects of cannabinoid agonists. Schild analysis has the potential for identifying receptor subtypes that mediate the in vivo effects of cannabinoid agonists.