The ability of ECBs to facilitate fear extinction is recapitulated by selective inhibition of FAAH. Rats infused with the FAAH inhibitor, URB597, into the mPFC prior to extinction training show improved extinction retrieval when subsequently tested drug-free [90]. More recently, systemic administration of a novel, potent FAAH inhibitor, AM3506 [100], prior to extinction training augmented extinction-induced BLA AEA levels and reduced fear on extinction retrieval in a mouse model of impaired extinction [50]. Although this drug did not reduce fear during extinction training, reduced fear on extinction retrieval is not contingent upon observable facilitation of extinction learning [94,101]. The effects of AM3506 were attributed to the BLA by the finding that infusing the drug directly into the BLA promoted extinction, and the demonstration that intra-BLA infusion of SR141716A blocked the pro-extinction effect of systemically delivered AM3506 [50]. Thus, these data show that CEA–CB1R signalling in the BLA is both necessary and sufficient for FAAH inhibitors to facilitate fear extinction. Interestingly, there is preliminary evidence that analogous effects may result from genetically driven variation in FAAH in human subjects (Box 3).
