(R)-Methanandamide and Δ⁹-tetrahydrocannabinol-induced operant rate decreases in rats are not readily antagonized by SR-141716A

The current study examined the interaction between the cannabinoid CB₁ receptor agonists Δ⁹-tetrahydrocannabinol and (R)-methanandamide in combination with the cannabinoid CB₁ receptor antagonist SR-141716A (N-(piperidin-1-yl)-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H- pyrazole-3-carboxamide HCl) in rats responding for food on a fixed ratio (FR-10) schedule of food reinforcement. The study provided only limited evidence for antagonism by SR-141716A (at 1 mg/kg but not with 0.3, 3 and 10 mg/kg) of the rate suppressant effects induced by the cannabinoid CB₁ receptor agonist Δ⁹-tetrahydrocannabinol (and only at the single dose of 5.6 mg/kg Δ⁹-tetrahydrocannabinol). (R)-Methanandamide in combination with SR-141716A resulted in a greater rate suppression compared to that induced by (R)-methanandamide alone. Thus, SR-141716A augmented the rate-decreasing effects of (R)-methanandamide and only minimally altered the rate-decreasing effects of Δ⁹-tetrahydrocannabinol. Additionally, high doses (10 and 30 mg/kg) of SR-141716 singly consistently suppressed the rate of responding. The current results coupled with our previous data examining combinations of Δ⁹-tetrahydrocannabinol or (R)-methanandamide and SR-141716 (see text) underscore pharmacological/behavioral differences (whether quantitative or qualitative) between the cannabinoid CB₁ agonists (R)-methanandamide and Δ⁹-tetrahydrocannabinol revealed by their interactions with the cannabinoid CB₁ antagonist SR-141716.