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

Molecular Psychiatry volume 18, pages 813–823 (2013)Cite this article

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Abstract

Endocannabinoids are released ‘on-demand’ on the basis of physiological need, and can be pharmacologically augmented by inhibiting their catabolic degradation. The endocannabinoid anandamide is degraded by the catabolic enzyme fatty acid amide hydrolase (FAAH). Anandamide is implicated in the mediation of fear behaviors, including fear extinction, suggesting that selectively elevating brain anandamide could modulate plastic changes in fear. Here we first tested this hypothesis with preclinical experiments employing a novel, potent and selective FAAH inhibitor, AM3506 (5-(4-hydroxyphenyl)pentanesulfonyl fluoride). Systemic AM3506 administration before extinction decreased fear during a retrieval test in a mouse model of impaired extinction. AM3506 had no effects on fear in the absence of extinction training, or on various non-fear-related measures. Anandamide levels in the basolateral amygdala were increased by extinction training and augmented by systemic AM3506, whereas application of AM3506 to amygdala slices promoted long-term depression of inhibitory transmission, a form of synaptic plasticity linked to extinction. Further supporting the amygdala as effect-locus, the fear-reducing effects of systemic AM3506 were blocked by intra-amygdala infusion of a CB1 receptor antagonist and were fully recapitulated by intra-amygdala infusion of AM3506. On the basis of these preclinical findings, we hypothesized that variation in the human FAAH gene would predict individual differences in amygdala threat-processing and stress-coping traits. Consistent with this, carriers of a low-expressing FAAH variant (385A allele; rs324420) exhibited quicker habituation of amygdala reactivity to threat, and had lower scores on the personality trait of stress-reactivity. Our findings show that augmenting amygdala anandamide enables extinction-driven reductions in fear in mouse and may promote stress-coping in humans.

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Acknowledgements

This work was supported by the NIAAA Intramural Research Program (OGC, KPM, RC, GK, AH), Department of Defense in the Center for Neuroscience and Regenerative Medicine (OGC, AH), NIA (AG032282 to TEM), MRC (G0100527 to TEM), NIDA (DA031579 to ARH) and NIMH (MH077874 to AC; MH072837 to ARH, MH090412 to SP). AC is a Royal Society Wolfson Merit Award holder. We thank Daniel Fisher and Caitlin Schaapveld for assistance with behavioral experiments.

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Authors and Affiliations

  1. Laboratory of Behavioral and Genomic Neuroscience, Section on Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, Bethesda, MD, USA

    O Gunduz-Cinar, K P MacPherson & A Holmes

  2. Center for Neuroscience and Regenerative Medicine at the Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    O Gunduz-Cinar

  3. Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA

    R Cinar, G Godlewski & G Kunos

  4. Department of Psychiatry and Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA

    J Gamble-George, T S Ramikie & S Patel

  5. Department of Psychology and Neuroscience, Duke University, Durham, NC, USA

    K Sugden, B Williams, A X Gorka, A R Hariri, A Caspi & T E Moffitt

  6. Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA

    K Sugden, B Williams, A Caspi & T E Moffitt

  7. Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA

    K Sugden, B Williams, A R Hariri, A Caspi & T E Moffitt

  8. Social, Genetic, and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, London, UK

    K Sugden, B Williams, A Caspi & T E Moffitt

  9. Center for Drug Discovery, Northeastern University, Boston, MA, USA

    S O Alapafuja, S P Nikas & A Makriyannis

  10. Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    R Poulton

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  1. O Gunduz-Cinar
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Gunduz-Cinar, O., MacPherson, K., Cinar, R. et al. Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol Psychiatry 18, 813–823 (2013). https://doi.org/10.1038/mp.2012.72

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