Enhancing Endocannabinoid Neurotransmission Augments The Efficacy of Extinction Training and Ameliorates Traumatic Stress-Induced Behavioral Alterations in Rats

Neuropsychopharmacology. 2018 May;43(6):1284-1296. doi: 10.1038/npp.2017.305. Epub 2017 Dec 21.


Exposure to a traumatic event may result in the development of post-traumatic stress disorder (PTSD). Endocannabinoids are crucial modulators of the stress response, interfere with excessive retrieval and facilitate the extinction of traumatic memories. Exposure therapy, combined with pharmacotherapy, represents a promising tool for PTSD treatment. We investigated whether pharmacological manipulations of the endocannabinoid system during extinction learning ameliorates the behavioral changes induced by trauma exposure. Rats were exposed to inescapable footshocks paired with social isolation, a risk factor for PTSD. One week after trauma, rats were subjected to three spaced extinction sessions, mimicking human exposure therapy. The anandamide hydrolysis inhibitor URB597, the 2-arachidonoylglycerol hydrolysis inhibitor JZL184 or the cannabinoid agonist WIN55,212-2 were administered before or after the extinction sessions. Rats were tested for extinction retention 16 or 36 days after trauma and 24-h later for social interaction. Extinction training alone reduced fear of the trauma-associated context but did not restore normal social interaction. Traumatized animals not exposed to extinction sessions exhibited reductions in hippocampal anandamide content with respect to home-cage controls. Noteworthy, all drugs exerted beneficial effects, but URB597 (0.1 mg/kg) induced the best improvements by enhancing extinction consolidation and restoring normal social behavior in traumatized rats through indirect activation of CB1 receptors. The ameliorating effects remained stable long after treatment and trauma exposure. Our findings suggest that drugs potentiating endocannabinoid neurotransmission may represent promising tools when combined to exposure-based psychotherapies in the treatment of PTSD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Amidohydrolases / metabolism
  • Animals
  • Arachidonic Acids / metabolism
  • Benzamides / pharmacology*
  • Benzodioxoles / pharmacology*
  • Benzoxazines / pharmacology*
  • Cannabinoid Receptor Modulators / pharmacology*
  • Carbamates / pharmacology*
  • Disease Models, Animal
  • Electroshock
  • Endocannabinoids / metabolism
  • Extinction, Psychological / drug effects*
  • Extinction, Psychological / physiology
  • Glycerides / metabolism
  • Male
  • Morpholines / pharmacology*
  • Naphthalenes / pharmacology*
  • Piperidines / pharmacology*
  • Psychotropic Drugs / pharmacology
  • Rats, Sprague-Dawley
  • Social Isolation
  • Stress Disorders, Post-Traumatic / drug therapy*
  • Stress Disorders, Post-Traumatic / metabolism
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology


  • Arachidonic Acids
  • Benzamides
  • Benzodioxoles
  • Benzoxazines
  • Cannabinoid Receptor Modulators
  • Carbamates
  • Endocannabinoids
  • Glycerides
  • JZL 184
  • Morpholines
  • Naphthalenes
  • Piperidines
  • Psychotropic Drugs
  • cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • glyceryl 2-arachidonate
  • Amidohydrolases
  • fatty-acid amide hydrolase