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Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice
Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0002-0645-4869
Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
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2020 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 25, no 5, p. 993-1005Article in journal (Refereed) Published
Abstract [en]

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-greater thanA 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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2020. Vol. 25, no 5, p. 993-1005
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Neurosciences
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URN: urn:nbn:se:liu:diva-154914DOI: 10.1038/s41380-018-0215-1ISI: 000529878300007PubMedID: 30120421Scopus ID: 2-s2.0-85052287102OAI: oai:DiVA.org:liu-154914DiVA, id: diva2:1293672
Note

Funding agencies: Swedish Research CouncilSwedish Research Council [2013-7434]; Canadian Institutes of Health Research (CIHR)Canadian Institutes of Health Research (CIHR); Alberta Innovates and BranchOut Neurological Foundation

Available from: 2019-03-05 Created: 2019-03-05 Last updated: 2021-05-07Bibliographically approved

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Mayo, Leah M.Asratian, AnnaLindé, JohanHolm, LovisaNätt, DanielAugier, GaëlleStensson, NiclasGhafouri, BijarHeilig, Markus

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Mayo, Leah M.Asratian, AnnaLindé, JohanHolm, LovisaNätt, DanielAugier, GaëlleStensson, NiclasGhafouri, BijarHeilig, Markus
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Center for Social and Affective NeuroscienceFaculty of Medicine and Health SciencesDivision of Prevention, Rehabilitation and Community MedicinePain and Rehabilitation CenterPsykiatriska kliniken i Linköping
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