Tags

Type your tag names separated by a space and hit enter

Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity.
Mol Psychiatry. 2013 Jul; 18(7):813-23.MP

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.

Authors+Show Affiliations

Laboratory of Behavioral and Genomic Neuroscience, Section on Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, Bethesda, MD, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

22688188

Citation

Gunduz-Cinar, O, et al. "Convergent Translational Evidence of a Role for Anandamide in Amygdala-mediated Fear Extinction, Threat Processing and Stress-reactivity." Molecular Psychiatry, vol. 18, no. 7, 2013, pp. 813-23.
Gunduz-Cinar O, MacPherson KP, Cinar R, et al. Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol Psychiatry. 2013;18(7):813-23.
Gunduz-Cinar, O., MacPherson, K. P., Cinar, R., Gamble-George, J., Sugden, K., Williams, B., Godlewski, G., Ramikie, T. S., Gorka, A. X., Alapafuja, S. O., Nikas, S. P., Makriyannis, A., Poulton, R., Patel, S., Hariri, A. R., Caspi, A., Moffitt, T. E., Kunos, G., & Holmes, A. (2013). Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Molecular Psychiatry, 18(7), 813-23. https://doi.org/10.1038/mp.2012.72
Gunduz-Cinar O, et al. Convergent Translational Evidence of a Role for Anandamide in Amygdala-mediated Fear Extinction, Threat Processing and Stress-reactivity. Mol Psychiatry. 2013;18(7):813-23. PubMed PMID: 22688188.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. AU - Gunduz-Cinar,O, AU - MacPherson,K P, AU - Cinar,R, AU - Gamble-George,J, AU - Sugden,K, AU - Williams,B, AU - Godlewski,G, AU - Ramikie,T S, AU - Gorka,A X, AU - Alapafuja,S O, AU - Nikas,S P, AU - Makriyannis,A, AU - Poulton,R, AU - Patel,S, AU - Hariri,A R, AU - Caspi,A, AU - Moffitt,T E, AU - Kunos,G, AU - Holmes,A, Y1 - 2012/06/12/ PY - 2012/6/13/entrez PY - 2012/6/13/pubmed PY - 2014/5/3/medline SP - 813 EP - 23 JF - Molecular psychiatry JO - Mol. Psychiatry VL - 18 IS - 7 N2 - 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. SN - 1476-5578 UR - https://www.unboundmedicine.com/medline/citation/22688188/Convergent_translational_evidence_of_a_role_for_anandamide_in_amygdala_mediated_fear_extinction_threat_processing_and_stress_reactivity_ L2 - http://dx.doi.org/10.1038/mp.2012.72 DB - PRIME DP - Unbound Medicine ER -