Figure 1 shows the results of tests with THC, anandamide, 2-AG, and the combinations of 0.3 mg/kg URB597/anandamide and 1 mg/kg NAM/2-AG in two groups of mice trained to discriminate 5.6 mg/kg THC from vehicle. As expected, dose-dependent substitution was observed with THC in both groups, with ED50 values of 2.27 (95% CI: 1.88 – 2.74) mg/kg and 2.40 (95% CI: 2.10 – 2.74) mg/kg for mice later tested with anandamide (Fig. 1, panel A) and 2-AG (Fig. 1, panel B), respectively. In contrast, neither endocannabinoid substituted for THC when evaluated alone or in combination with an inhibitor of its primary metabolic enzyme, the FAAH inhibitor URB597 (Fig. 1, panel A) or the nonselective MAGL inhibitor NAM (Fig. 1, panel B) for anandamide and 2-AG, respectively. Further, neither URB597 (0.3 mg/kg) nor NAM (1 mg/kg) substituted for THC when administered alone, as shown at the left side of panels A and B, respectively. Response rates following administration of any of the doses of THC did not significantly differ from rates obtained after vehicle injection for either discrimination group (Fig. 1,
