Together with previous results, the present results suggest a complex interplay between anandamide and 2-AG in producing THC-like discriminative stimulus effects. Anandamide typically does not substitute for THC unless its rapid metabolism by FAAH is inhibited through pharmacological or genetic means (Solinas et al., 2007; Vann et al., 2009; Walentiny et al., 2011). Notably, however, flooding of the system by exogenous administration of anandamide is generally necessary for this substitution to occur; i.e., FAAH inhibitors increase anandamide concentration in the brain, but when administered alone, do not substitute for THC. Further, FAAH(−/−) mice have elevated brain concentration of anandamide, but do not show a distinct phenotype suggestive of a persistent THC-like state (Cravatt et al., 2001). In contrast with the anandamide profile, endogenous increases in 2-AG (e.g., through administration of JZL184) produced substantial substitution for THC even in the absence 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
