Disruption of FAAH and AEA may be exacerbated under conditions of chronic stress. Rodents exposed to chronic stress show sustained enhancement of FAAH activity and prolonged reductions in tissue levels of BLA AEA that persist beyond exposure [59,68,69]. Additionally, multiple studies have found that chronic stress results in an increase in dendritic arborization and spinogenesis on BLA pyramidal neurons, increasing their intrinsic excitability and afferent stimulation in a manner that correlates with heightened anxiety-like behavior [70–72]. These morphological changes are absent in mutant mice lacking FAAH [68], whereas genetic loss or repeated, pre-stress pharmacological inhibition (JNJ5003) of FAAH prevents stress-induced reductions in AEA and increases in HPA activity and anxiety-like behavior [68,73,74]. Accordingly, inhibition of FAAH can potently ameliorate multiple sequelae of chronic stress by enhancing AEA signaling and restoring BLA dysfunction (Figure 1).
