In contrast with increased substitution produced by anandamide and PF3845, URB597 failed to enhance substitution of anandamide for THC in mice and did not substitute on its own in either mice or rats, regardless of THC training dose. Given that URB597 has been shown to enhance anandamide’s substitution for THC in rats (Solinas et al., 2007), the present results may represent a species difference. Of note, however, 0.3 mg/kg URB597 increased cerebellar concentration of anandamide (but not 2-AG) and accentuated anandamide-stimulated CB1 receptor activation, confirming that it was an effective inhibitor of FAAH. Hence, a more likely explanation URB597’s failure to potentiate anandamide substitution for THC is the exquisite sensitivity to anandamide-induced decreases in response rates observed in THC-trained mice in Experiment 1, an effect that was not observed in Experiment 2. A response rate criterion (≥ 0.16 responses/s) implemented in the acquisition training of mice may have prevented a floor effect in response rate data in Experiment 2. Enhanced sensitivity of the mice in Experiment 1 appeared to be selective for endocannabinoids rather than for all cannabinoid agonists, as
