Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype

Biol Psychiatry. 2017 Oct 1;82(7):500-510. doi: 10.1016/j.biopsych.2017.01.005. Epub 2017 Jan 13.


Background: Corticotropin-releasing factor (CRF) mediates anxiogenic responses by activating CRF type 1 (CRF1) receptors in limbic brain regions. Anxiety is further modulated by the endogenous cannabinoid (eCB) system that attenuates the synaptic effects of stress. In the amygdala, acute stress activates the enzymatic clearance of the eCB N-arachidonoylethanolamine via fatty acid amide hydrolase (FAAH), although it is unclear whether chronic dysregulation of CRF systems induces maladaptive changes in amygdalar eCB signaling. Here, we used genetically selected Marchigian Sardinian P (msP) rats carrying an innate overexpression of CRF1 receptors to study the role of constitutive upregulation in CRF systems on amygdalar eCB function and persistent anxiety-like effects.

Methods: We applied behavioral, pharmacological, and biochemical methods to broadly characterize anxiety-like behaviors and amygdalar eCB clearance enzymes in msP versus nonselected Wistar rats. Subsequent studies examined the influence of dysregulated CRF and FAAH systems in altering excitatory transmission in the central amygdala (CeA).

Results: msPs display an anxious phenotype accompanied by elevations in amygdalar FAAH activity and reduced dialysate N-arachidonoylethanolamine levels in the CeA. Elevations in CRF-CRF1 signaling dysregulate FAAH activity, and this genotypic difference is normalized with pharmacological blockade of CRF1 receptors. msPs also exhibit elevated baseline glutamatergic transmission in the CeA, and dysregulated CRF-FAAH facilitates stress-induced increases in glutamatergic activity. Treatment with an FAAH inhibitor relieves sensitized glutamatergic responses in msPs and attenuates the anxiety-like phenotype.

Conclusions: Pathological anxiety and stress hypersensitivity are driven by constitutive increases in CRF1 signaling that dysregulate N-arachidonoylethanolamine signaling mechanisms and reduce neuronal inhibitory control of CeA glutamatergic synapses.

Keywords: Anxiety; CRF1; Central amygdala (CeA); Endocannabinoid; Excitatory; Glutamate.

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Amidohydrolases / metabolism*
  • Amygdala / drug effects
  • Amygdala / metabolism*
  • Animals
  • Anxiety / drug therapy
  • Anxiety / pathology*
  • Cannabinoids / metabolism
  • Corticotropin-Releasing Hormone / metabolism*
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Exploratory Behavior / drug effects
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Male
  • Maze Learning / drug effects
  • Neurotransmitter Agents / metabolism
  • Patch-Clamp Techniques
  • Piperidines / pharmacology
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • Rats
  • Rats, Mutant Strains
  • Receptors, Corticotropin-Releasing Hormone / genetics
  • Receptors, Corticotropin-Releasing Hormone / metabolism


  • Cannabinoids
  • Enzyme Inhibitors
  • N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo(1,5-a)pyrimidin-7-amine
  • Neurotransmitter Agents
  • PF 3845
  • Piperidines
  • Pyridines
  • Pyrimidines
  • Receptors, Corticotropin-Releasing Hormone
  • CRF receptor type 1
  • Corticotropin-Releasing Hormone
  • Amidohydrolases
  • fatty-acid amide hydrolase