Post-traumatic stress disorder (PTSD) is a common, debilitating condition with limited treatment options. Extinction of fear memories through prolonged exposure therapy, the primary evidence-based behavioral treatment for PTSD, has only partial efficacy. In mice, pharmacological inhibition of fatty acid amide hydrolase (FAAH) produces elevated levels of anandamide (AEA) and promotes fear extinction, suggesting that FAAH inhibitors may aid fear extinction-based treatments. A human FAAH 385C->A substitution encodes an FAAH enzyme with reduced catabolic efficacy. Individuals homozygous for the FAAH 385A allele may therefore offer a genetic model to evaluate the impact of elevations in AEA signaling in humans, helping to inform whether FAAH inhibitors have the potential to facilitate fear extinction therapy for PTSD. To overcome the challenge posed by low frequency of the AA genotype (appr. 5%), we prospectively genotyped 423 individuals to examine the balanced groups of CC, AC, and AA individuals (n = 25/group). Consistent with its loss-of-function nature, the A allele was dose dependently associated with elevated basal AEA levels, facilitated fear extinction, and enhanced the extinction recall. Moreover, the A-allele homozygotes were protected against stress-induced decreases in AEA and negative emotional consequences of stress. In a humanized mouse model, AA homozygous mice were similarly protected against stress-induced decreases in AEA, both in the periphery, and also in the amygdala and prefrontal cortex, brain structures critically involved in fear extinction and regulation of stress responses. Collectively, these data suggest that AEA signaling can temper aspects of the stress response and that FAAH inhibition may aid the treatment for stress-related psychiatric disorders, such as PTSD.
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The authors are grateful to Åsa Axén and Gisela Öhnström for their invaluable effort in participant screening, Matilda Areskoug for aid in data collection, and Dr. Margaret Wardle for continued technical assistance. The authors would like to acknowledge the Southern Alberta Mass Spectrometry Centre, located in and supported by the Cumming School of Medicine, University of Calgary, for their services in targeted liquid chromatography tandem mass spectrometry. This work was funded by the Swedish Research Council grant 2013-7434 to MH and grants from the Canadian Institutes of Health Research (CIHR) to MNH. HAV is a Vanier Scholar (CIHR) and receives studentships from the Alberta Innovates and BranchOut Neurological Foundation and GB is a Killam Scholar (CIHR).
Conflict of interest
MNH receives salary support from CIHR in the form of a tier II Canada Research Chair. MNH has done consulting for both Pfizer and GW Pharmaceuticals.
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Mayo, L.M., Asratian, A., Lindé, J. et al. Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice. Mol Psychiatry 25, 993–1005 (2020). https://doi.org/10.1038/s41380-018-0215-1
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