Endocannabinoid-mediated improvement on a test of aversive memory in a mouse model of fragile X syndrome

Behav Brain Res. 2015 Sep 15:291:164-171. doi: 10.1016/j.bbr.2015.05.003. Epub 2015 May 12.


Silencing the gene FMR1 in fragile X syndrome (FXS) with consequent loss of its protein product, FMRP, results in intellectual disability, hyperactivity, anxiety, seizure disorders, and autism-like behavior. In a mouse model (Fmr1 knockout (KO)) of FXS, a deficit in performance on the passive avoidance test of learning and memory is a robust phenotype. We report that drugs acting on the endocannabinoid (eCB) system can improve performance on this test. We present three lines of evidence: (1) Propofol (reported to inhibit fatty acid amide hydrolase (FAAH) activity) administered 30 min after training on the passive avoidance test improved performance in Fmr1 KO mice but had no effect on wild type (WT). FAAH catalyzes the metabolism of the eCB, anandamide, so its inhibition should result in increased anandamide levels. (2) The effect of propofol was blocked by prior administration of the cannabinoid receptor 1 antagonist AM-251. (3) Treatment with the FAAH inhibitor, URB-597, administered 30 min after training on the passive avoidance test also improved performance in Fmr1 KO mice but had no effect on WT. Our results indicate that the eCB system is involved in FXS and suggest that the eCB system is a promising target for treatment of FXS.

Keywords: FAAH; Fmr1 KO mice; Fragile X syndrome; Memory; Passive avoidance; Propofol.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Amidohydrolases / metabolism
  • Animals
  • Anxiety / drug therapy
  • Anxiety / metabolism
  • Arachidonic Acids / metabolism*
  • Avoidance Learning / drug effects
  • Avoidance Learning / physiology*
  • Benzamides / pharmacology
  • Cannabinoid Receptor Antagonists / pharmacology
  • Carbamates / pharmacology
  • Disease Models, Animal
  • Endocannabinoids / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism
  • Fragile X Syndrome / drug therapy
  • Fragile X Syndrome / metabolism*
  • Male
  • Memory / drug effects
  • Memory / physiology*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Piperidines / pharmacology
  • Polyunsaturated Alkamides / metabolism*
  • Propofol / pharmacology
  • Pyrazoles / pharmacology
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Receptors, GABA-A / metabolism
  • Social Behavior


  • Arachidonic Acids
  • Benzamides
  • CNR1 protein, mouse
  • Cannabinoid Receptor Antagonists
  • Carbamates
  • Endocannabinoids
  • Enzyme Inhibitors
  • Fmr1 protein, mouse
  • Piperidines
  • Polyunsaturated Alkamides
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Receptors, GABA-A
  • cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
  • Fragile X Mental Retardation Protein
  • AM 251
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • anandamide
  • Propofol