of exogenous flooding of the system with 2-AG. Further, MAGL(−/−) mice have both elevated brain concentrations of 2-AG and an altered phenotype suggestive of chronic stimulation of CB1 receptors (Schlosburg et al., 2010). These results suggest that endogenous increases in 2-AG may be more effective in inducing THC-like discriminative stimulus effects in mice than are endogenous increases in anandamide. Nevertheless, full substitution required addition of endogenous increases in anandamide via FAAH inhibition [through a dual inhibitor, JZL195, or JZL184 in FAAH(−/−) mice] (Long et al., 2009c). The lack of significant substitution of JZL184 alone in rats may be related to a species difference in compound potency (e.g., see Long et al., 2009b), to an insufficient dose (e.g., see mouse data), and/or to differences in training dose. Alternatively, JZL184 also inhibits FAAH, though its acute administration does not elevate whole brain anandamide concentrations (Long et al., 2009b). Consistent with this hypothesis, a novel MAGL inhibitor with increased selectivity (KML29) produced minimal substitution for THC in mice trained to discriminate THC (Ignatowska-Jankowska et al., 2014), but fully substituted for anandamide in FAAH (−/−) mice, an effect that was rimonabant reversible (Ignatowska-Jankowska et al., 2014).
