Disruption of fatty acid amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure

Mol Psychiatry. 2013 Oct;18(10):1125-35. doi: 10.1038/mp.2012.90. Epub 2012 Jul 10.


Hyperactivation of the amygdala following chronic stress is believed to be one of the primary mechanisms underlying the increased propensity for anxiety-like behaviors and pathological states; however, the mechanisms by which chronic stress modulates amygdalar function are not well characterized. The aim of the current study was to determine the extent to which the endocannabinoid (eCB) system, which is known to regulate emotional behavior and neuroplasticity, contributes to changes in amygdalar structure and function following chronic stress. To examine the hypothesis, we have exposed C57/Bl6 mice to chronic restraint stress, which results in an increase in fatty acid amide hydrolase (FAAH) activity and a reduction in the concentration of the eCB N-arachidonylethanolamine (AEA) within the amygdala. Chronic restraint stress also increased dendritic arborization, complexity and spine density of pyramidal neurons in the basolateral nucleus of the amygdala (BLA) and increased anxiety-like behavior in wild-type mice. All of the stress-induced changes in amygdalar structure and function were absent in mice deficient in FAAH. Further, the anti-anxiety effect of FAAH deletion was recapitulated in rats treated orally with a novel pharmacological inhibitor of FAAH, JNJ5003 (50 mg per kg per day), during exposure to chronic stress. These studies suggest that FAAH is required for chronic stress to induce hyperactivity and structural remodeling of the amygdala. Collectively, these studies indicate that FAAH-mediated decreases in AEA occur following chronic stress and that this loss of AEA signaling is functionally relevant to the effects of chronic stress. These data support the hypothesis that inhibition of FAAH has therapeutic potential in the treatment of anxiety disorders, possibly by maintaining normal amygdalar function in the face of chronic stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / deficiency
  • Amidohydrolases / genetics
  • Amidohydrolases / physiology*
  • Amygdala / metabolism
  • Amygdala / pathology*
  • Animals
  • Anxiety / enzymology
  • Anxiety / etiology
  • Anxiety / prevention & control*
  • Arachidonic Acids
  • Chronic Disease
  • Cyclohexanols / pharmacology
  • Dendrites / ultrastructure
  • Drug Evaluation, Preclinical
  • Endocannabinoids / deficiency
  • Endocannabinoids / metabolism
  • Exploratory Behavior / drug effects
  • Male
  • Maze Learning / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Polyunsaturated Alkamides
  • Pyramidal Cells / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / physiology
  • Restraint, Physical / adverse effects
  • Stress, Psychological / complications
  • Stress, Psychological / enzymology*
  • Stress, Psychological / pathology
  • Stress, Psychological / physiopathology


  • Arachidonic Acids
  • Cyclohexanols
  • Endocannabinoids
  • Polyunsaturated Alkamides
  • Receptor, Cannabinoid, CB1
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • anandamide