AEA elevation, via FAAH inhibition or genetic deletion, has been reported to have anxiolytic-like effects in exploratory models of anxiety, such as the zero maze (Kathuria et al., 2003), elevated plus maze (Moreira et al., 2008; Naidu et al., 2007; Patel and Hillard, 2006), and light/dark box (Moreira et al., 2008). However, the effects of 2-AG on anxiety have been difficult to ascertain, due to its rapid in vivo metabolism, until the recent synthesis of JZL184. Although MAGL is the primary enzyme responsible for 85% of 2-AG catabolism, other enzymes such as ABHD6 and ABHD12 contribute to 2-AG degradation, and these enzymes have distinct intracellular distributions (Blankman et al., 2007). Thus, it is possible that inhibition of these minor 2-AG catabolic enzymes may also have consequences on anxiety-related behavior that differ from MAGL inhibition.
