Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Δ9-tetrahydrocannabinol

Rationale Drug discrimination can be used to examine tolerance and dependence in agonist-treated animals by establishing an appropriate antagonist as a discriminative stimulus. Objective Establish intravenous SR 141716A as a discriminative stimulus in four rhesus monkeys pretreated with a relatively small dose of Delta(9)-tetrahydrocannabinol (Delta(9)-THC). Methods Rhesus monkeys received i.v. Delta(9)-THC (0.32 mg/kg) and discriminated i.v. SR 141716A (1 mg/kg) from vehicle while responding under a fixed ratio (FR) 5 schedule of stimulus-shock termination. Results The discriminative stimulus effects of SR 141716A were dose-dependent (ED50 = 0.33 mg/kg) and were mimicked by the CB1 antagonist AM 251 (ED50 = 0.98 mg/kg), but not by a benzodiazepine (midazolam) or an N-methyl-D-aspartate antagonist (ketamine). An additional dose (0.32 mg/kg in addition to 0.32 mg/kg administered before the session) of Delta(9)-THC shifted the SR 141716A dose effect curve 3-fold rightward. Omitting Delta(9)-THC before test sessions resulted in responding on the SR 141716A lever that was attenuated by subsequent administration of Delta(9)-THC (ED50 = 0.13 mg/kg), CP 55940 (ED50 = 0.013 mg/kg), and WIN 55212-2 (ED50 = 0.35 mg/kg); midazolam and ketamine did not attenuate responding on the SR 141716A lever. SR 141716A (1 mg/kg) shifted the Delta(9)-THC and CP 55940 dose-effect curves 3.4-fold rightward; the WIN 55212-2 dose-effect curve was not significantly modified by a dose of 1 mg/kg of SR 141716A. Conclusions SR 141716A can be established as a discriminative stimulus in animals pretreated with Delta(9)-THC, and this assay is selective for cannabinoid activity. Differential antagonism of cannabinoids by SR 141716A might indicate that the mechanism of action of WIN 55212-2 is not identical to other cannabinoids. This study demonstrates that, under the appropriate conditions, drug discrimination has utility for examining cannabinoid dependence and withdrawal.