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    • Collectively these observations demonstrate that

    2022-05-24

    Collectively, these observations demonstrate that FAAH is functionally positioned to modulate the actions of AEA and other NAEs on BLA neurons and anxiety processes mediated by this region. By extension, manipulations that lead to alterations in FAAH activity, such as stress or administration of compounds targeting FAAH [52], would be predicted to functionally impact BLA functions, including anxiety. We consider emerging evidence in support of this hypothesis in the next section.
    FAAH modulation of anxiety and stress There is growing evidence that tonic ECB signaling in the BLA and elsewhere is mediated by AEA, whereas phasic ECB responses to robust neuronal activation are subserved by 2-AG 53, 54, 55, 56. Interestingly, stress appears to produce divergent effects on AEA and 2-AG levels in the BLA – with an elevation in 2-AG levels [57], but a rapid induction of FAAH activity and a resultant decline in the pool of AEA 58, 59, 60 were reported following exposure to various types of stress. These differing directional and temporal responses probably indicate a difference in the mechanisms modulating the effects of these two ECBs and their catabolic Nicardipine HCl in the BLA. These mechanisms are not currently understood, however, and it is also unclear exactly how the relative balance between changes in AEA and 2-AG impacts the response and recovery from stress. Notwithstanding, several recent observations demonstrate that loss of AEA–CB1R signaling in the BLA can trigger behavioral and neuroendocrine responses to stress. First, presumably by removing AEA-mediated tonic inhibitory activity, CB1R antagonism increases BLA excitability 61, 62, 63, activates the hypothalamic–pituitary–adrenal (HPA) axis and increases anxiety-like behavior 58, 64, 65. Second, increasing AEA by inhibiting FAAH (with URB597) reduces the HPA axis and anxiety-like response to stress 58, 66. These actions of FAAH inhibition have been localized to actions specifically within the BLA by the finding that only infusion of URB597 into the BLA, and not CeA or medial amygdala, is effective in producing these anti-stress effects [58]. Collectively, these findings support a model in which stress rapidly mobilizes FAAH, depletes the signaling pool of AEA, and increases BLA excitability to drive anxiety [67] (Figure 1). 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 Nicardipine HCl 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, 71, 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). The contribution of BLA 2-AG to stress responsivity and recovery remains, in contrast to FAAH–AEA signaling, much less certain at the present time. As noted above, stress increases 2-AG in the BLA, which could suggest a protective/restorative role to counter the effects of stress-induced AEA depletion. In this context, systemically administered MAGL inhibitors have been shown to acutely reduce anxiety-like behavior 75, 76, 77, 78, and when administered chronically, to prevent chronic stress-induced increases in anxiety-like behavior and impairments in BLA synaptic plasticity [75]. Further studies will be needed to determine the role of MAGL–2-AG signaling in moderating stress and the manner in which this mechanism interacts with the FAAH–AEA system in the BLA. Indeed, these relationships may be further complicated by sex differences in the ECB system and ECB mediation of anxiety (Box 2).