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A translational study for the role of anandamide and FAAH in fear extinction, threat processing and stress-reactivity

Thursday, October 11, 2012 — Poster Session IV

2:00 p.m. – 4:00 p.m.

Natcher Conference Center, Building 45



* FARE Award Winner


  • O. Gunduz-Cinar
  • K.P. MacPherson
  • R. Cinar
  • J. Gamble-George
  • K. Sugden
  • B. Williams
  • G. Godlewski
  • T.S. Ramikie
  • A.X Gorka
  • S.O. Alapafuja
  • S.P. Nikas
  • A. Makriyannis
  • R. Poulton
  • S. Patel
  • A.R. Hariri
  • A. Caspi
  • T.E. Moffitt
  • G. Kunos
  • A. Holmes


Endocannabinoid anandamide is implicated in the mediation of fear behaviors, suggesting that selectively elevating brain anandamide by inhibiting its catabolic enzyme fatty acid amide hydrolase (FAAH) could modulate plastic changes in fear. We first tested this with preclinical experiments employing a novel, potent and selective FAAH inhibitor, AM3506. Systemic AM3506 administration prior to 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 basolateral amygdala were increased by extinction training and augmented by systemic AM3506, while application of AM3506 to amygdala slices promoted long-term depression of inhibitory transmission. Furthermore, systemic AM3506 effects were blocked by intra-amygdala infusion of a CB1R antagonist and were fully recapitulated by intra-amygdala infusion of AM3506. Based on these, we hypothesized that variation in 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 (C385A; rs324420) exhibited quicker habituation of amygdala reactivity to threat, and had lower scores on personality trait stress-reactivity. In conclusion boosting anandamide enables extinction-driven fear reductions in mouse and may promote stress-coping in humans.

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