Amygdala FAAH and anandamide: mediating protection and recovery from stress

Abstract

A long-standing literature linking endocannabinoids (ECBs) to stress, fear, and anxiety has led to growing interest in developing novel anxiolytics targeting the ECB system. Following rapid on-demand biosynthesis and degradation upon neuronal activation, the ECB N-arachidonoylethanolamide (anandamide, AEA) is actively degraded by the serine hydrolase enzyme, fatty acid amide hydrolase (FAAH). Exposure to stress rapidly mobilizes FAAH to deplete the signaling pool of AEA and increase neuronal excitability in a key anxiety-mediating region--the basolateral amygdala (BLA). Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety-like behavior. Additionally, inhibition of FAAH facilitates long-term fear extinction and rescues deficient fear extinction in rodent models by enhancing AEA-CB1 (cannabinoid type 1) receptor signaling and synaptic plasticity in the BLA. These preclinical findings propose restoring deficient BLA AEA levels by pharmacologically inhibiting FAAH as a mechanism to therapeutically mitigate the effects of traumatic stress.

Keywords: 2-AG; anxiety; depression; endocannabinoid; fear; post-traumatic stress disorder.

Figure 1

Role of FAAH in the pathophysiology and therapeutic alleviation of stress-induced anxiety. Hypothesized pathophysiological scheme by which stress activates FAAH, leading to depletion of AEA in the BLA, a reduction in CB1R signaling and dendritic hypertrophy associated with anxiety. Therapeutic alleviation of stress-induced anxiety could be achieved by inhibiting FAAH to increase BLA AEA levels to restore CB1R signaling and possibly normalize dendritic abnormal morphology. Abbreviations: FAAH, fatty acid amide hydrolase; AEA, anandamide; BLA, basolateral amygdala; CB1R, cannabinoid receptor type 1.

Figure 2

Putative mechanism mediating fatty acid amide hydrolase (FAAH) inhibitor effects on fear extinction. Following formation of a fear memory, systemic administration of a FAAH inhibitor increases anandamide (AEA) levels in the basolateral amygdala (BLA) and increases cannabinoid receptor type 1 (CB1R) signaling to enhance attenuation of GABAergic transmission via long-term depression of inhibitory transmission (LTDi) [50]. Lesser inhibition may remove a brake on the activity/plasticity of BLA neurons [102] recruited to encode extinction, allowing FAAH to gate the formation of extinction memories.