Cannabinoid agonists differentially substitute for the discriminative stimulus effects of Δ⁹-tetrahydrocannabinol in C57BL/6J mice

Rationale: A variety of behavioral procedures have been developed to assess cannabinoid activity in mice; however, the feasibility of establishing Δ⁹-THC as a discriminative stimulus in mice has not been documented. Objective: One goal was to establish Δ⁹-THC as a discriminative stimulus in mice; after having done so, another goal was to examine the in vivo mechanism of action of Δ⁹-THC with other cannabinoids and noncannabinoids. Materials and methods: C57BL/6J mice (n=8) were trained to discriminate Δ⁹-THC (10 mg/kg i.p.) from vehicle while responding under a fixed ratio 30 schedule of food presentation. Results: Mice satisfied the discrimination criteria in 18-98 (median=67) sessions and the discriminative stimulus effects of Δ⁹-THC were dose-dependent (ED₅₀=2.6 mg/kg). CP 55940 and WIN 55212-2 dose-dependently increased Δ⁹-THC-appropriate responding to 100% (ED₅₀=0.032 and 0.45 mg/kg, respectively), whereas methanandamide and a variety of noncannabinoids (cocaine, ethanol, and ketamine) produced a maximum of 34% Δ⁹-THC-appropriate responding. The cannabinoid CB₁ antagonist SR 141716A (rimonabant) surmountably antagonized the discriminative effects of Δ⁹-THC, CP 55940, and WIN 55212-2; methanandamide did not significantly modify the Δ⁹-THC discriminative stimulus. Conclusions: The discriminative stimulus effects of Δ⁹-THC, CP 55940, and WIN 55212-2 are mediated by the same (i.e., CB₁) receptors, whereas the effects of methanandamide or a metabolite of methanandamide are mediated at least in part by non-CB₁ receptors. The discriminative stimulus effects of Δ⁹-THC in mice could be used to evaluate mechanisms of cannabinoid activity with approaches (e.g., inducible knockouts) currently unavailable in nonmurine species.