Partial agonist-like profile of the cannabinoid receptor antagonist SR141716A in a food-reinforced operant paradigm

Both cannabinoid CB, receptor agonists, such as Delta(9)-tetrahydrocannabinol (Delta(9)-THC), CP 55,940 and WIN 55,212-2, and the antagonist/inverse agonist SR141716A, dose-dependently suppress operant behavior. The present study investigated to what extent combined i.p. application of SR141716A with these cannabinoids resulted in mutually antagonistic effects, in additive effects, or in no interactive effects on operant responding in rats trained in a fixed-ratio 10, food-reinforced 10-min procedure. Pretreatment with SR141716A either had no effect on (at 0.3-1 mg/kg), or partially blocked (at 3 mg/kg), the inhibitory effects on responding induced by Delta(9)-THC (3-5 mg/kg) and CP 55,940 (0.03-0.2 mg/kg). Interestingly, while 3 mg/kg SR141716A induced moderate inhibitory effects on operant responding, its combination with either agonist resulted in the same level of inhibitory activity on responding as that obtained by SR141716A when tested alone. Pretreatment with a low dose of CP 55,940 (0.01 mg/kg) or WIN 55,212-2 (0.3 mg/kg) did not affect response inhibition induced by SR141716A. Combination of SR141716A (0.5 and 1 mg/kg) with Delta(9)-THC (3 mg/kg) resulted in the same level of response inhibition, independently of whether SR141716A was given 5 min before or 15 min after Delta(9)-THC. Although alternative explanations are conceivable, the data may indicate that SR141716A is a partial agonist at those cannabinoid receptors mediating the response-rate suppressive effects of cannabinoids.