Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity

With chronic drug exposure, endocannabinoid neuroadaptations that modulate stress responses may contribute to enhanced stress reactivity in addiction.

“In particular, with chronic drug exposure, neuro-adaptations in the endocannabinoid system, which modulates the response of the brain to stress,85 might contribute to the enhanced stress reactivity in addiction.”

Inhibition of FAAH could represent a risk variant for stressor-related psychiatric disorders.

“This work was furthered by Gunduz-Cinar et al. (84, 85) who showed that inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes the endogenous cannabinoid anandamide, enhances extinction learning in rodents and could represent a risk variant for stressor-related psychiatric disorders (84, 85).”

Inhibition of fatty acid amide hydrolase (FAAH) enhances extinction learning in rodents.

“This work was furthered by Gunduz-Cinar et al. (84, 85) who showed that inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes the endogenous cannabinoid anandamide, enhances extinction learning in rodents and could represent a risk variant for stressor-related psychiatric disorders (84, 85).”

Inhibition of FAAH facilitates long-term fear extinction and rescues deficient fear extinction in rodent models by enhancing AEA-CB1 receptor signaling and synaptic plasticity in the BLA.

“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.”

CB1R signaling generated by increased AEA can produce long-term depression of inhibitory transmission in the BLA, a change in synaptic plasticity which can serve to promote excitability.

“By contrast, CB1R signaling generated by increased AEA can also produce long-term depression of inhibitory transmission in the BLA, a change in synaptic plasticity which can serve to promote excitability [50,51].”

AEA released during extinction relieves a tonic inhibitory brake on BLA output neurons necessary for the encoding of extinction memories.

“This suggests a scheme in which AEA released during extinction relieves a tonic inhibitory brake on BLA output neurons [50,51,86] necessary for the encoding of extinction memories [102] (Figure 2).”

Systemic administration of AM3506 prior to extinction training augmented extinction-induced BLA AEA levels and reduced fear on extinction retrieval in a mouse model of impaired extinction.

“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].”

The effects of AM3506 were attributed to the BLA by the finding that infusing the drug directly into the BLA promoted extinction, and intra-BLA infusion of SR141716A blocked the pro-extinction effect of systemically delivered AM3506.

“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].”

A CB1R-dependent form of synaptic plasticity in the BLA, long-term depression of inhibitory GABAergic transmission (LTDi), is enhanced by FAAH knockout and by the FAAH inhibitor AM3506 at doses that promote extinction.

“One notable finding is that a CB1R-dependent form of synaptic plasticity in BLA [51,86], long-term depression of inhibitory GABAergic transmission (LTDi), is enhanced by FAAH KO [51] and by the FAAH inhibitor AM3506 at doses that promote extinction [50].”