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 Δ⁹-tetrahydrocannabinol (Δ⁹-THC; 0.1 mg/kg i.v.) discriminative stimulus and examined antagonism of cannabinoid agonists in rhesus monkeys. High levels of responding on the Δ⁹-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] > Δ⁹-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 Δ⁹-THC lever responding. The CB₁-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 Δ⁹-THC and CP 55940, and Schild analysis was consistent with a simple, competitive interaction (apparent pA₂ 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 Δ⁹-THC, CP 55940, and WIN 55212-2, and Schild analysis was consistent with a simple, competitive interaction (apparent pA₂ values were 6.3, 6.1, and 6.2, respectively). The CB₂-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 Δ⁹-THC discriminative stimulus. These results demonstrate that the discriminative stimulus effects of Δ⁹-THC are selective for cannabinoid activity, and the results of Schild analysis suggest that the same receptors mediate the discriminative stimulus effects of Δ⁹-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.