Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats

Eur Neuropsychopharmacol. 2008 Dec;18(12):849-59. doi: 10.1016/j.euroneuro.2008.07.001. Epub 2008 Aug 15.


The present study investigated the central effects of the eCB uptake/metabolism inhibitor AM404 and the phytocannabinoid cannabidiol (CBD) on the extinction of contextual fear memories in rats. Rats were conditioned and 24 h later subjected to three consecutive 9-min non-reinforced exposures to the conditioning context (extinction sessions, 24 h intervals). AM404 or CBD was injected i.c.v. 5 min before each extinction session and a 3-min drug-free test of contextual memory was performed 24 h after the last extinction session. AM404 (1.0 microg/microl, i.c.v.) and CBD (2.0 microg/microl, i.c.v.) facilitated extinction of contextual fear memory, with persistent effects. These responses were antagonized by the CB1-selective antagonist SR141716A (0.2 mg/kg, i.p.), but not by the TRPV1-selective antagonist capsazepine (5.0 microg/microl, i.c.v.). The effect of the anxiolytic drug Diazepam (DZP) on the extinction of contextual fear memory was also investigated. In contrast with the CBD and AM404 results, DZP induced a general reduction in the expression of conditioned freezing. Both AM404 and CBD induced anti-anxiogenic effect in the fear-potentiated plus-maze test, whereas DZP was anxiolytic in conditioned and unconditioned rats. In conclusion, CBD, a non-psychoactive phytocannabinoid could be an interesting pharmacological approach to reduce the anxiogenic effects of stress and promote the extinction of fear memories.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Arachidonic Acids / pharmacology*
  • Behavior, Animal / drug effects
  • Cannabidiol / antagonists & inhibitors
  • Cannabidiol / pharmacology*
  • Capsaicin / analogs & derivatives
  • Capsaicin / pharmacology
  • Conditioning, Psychological / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Extinction, Psychological / drug effects*
  • Fear*
  • Freezing Reaction, Cataleptic / drug effects
  • Injections, Intraventricular / methods
  • Male
  • Maze Learning / drug effects
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Wistar
  • Rimonabant
  • TRPV Cation Channels / antagonists & inhibitors


  • Anti-Anxiety Agents
  • Arachidonic Acids
  • Piperidines
  • Pyrazoles
  • TRPV Cation Channels
  • Cannabidiol
  • capsazepine
  • Rimonabant
  • Capsaicin
  • N-(4-hydroxyphenyl)arachidonylamide