In summary, elicitation of THC-like discriminative stimulus effects requires a complex interplay between anandamide and 2-AG. Although anandamide has been shown to substitute fully for THC, exogenous administration plus inhibition of its metabolism by FAAH is necessary. Endogenous increase in anandamide concentration via FAAH inhibition is not sufficient. In contrast, endogenous increase in 2-AG concentration may be more effective in promoting THC-like discriminative stimulus effects, as suggested by the partial substitution observed with JZL184 in THC-trained mice. Most effective, however, appears to be endogenous increases in both anandamide and 2-AG. The variable results across specific FAAH and MAGL inhibitors emphasizes the need for optimization of selectivity of pharmacological tools as well as testing of new models (e.g., MAGL knockout mice) in the discrimination paradigm.
