title: Endocannabinoid-mediated improvement on a test of aversive memory in a mouse model of fragile X syndrome.
abstract: 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.
authors.affiliation: Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bldg. 10, Rm. 2D54, Bethesda, MD 20892, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Qin
authors.affiliation: Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bldg. 10, Rm. 2D54, Bethesda, MD 20892, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Zeidler
authors.affiliation: Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bldg. 10, Rm. 2D54, Bethesda, MD 20892, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Moulton
authors.affiliation: Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bldg. 10, Rm. 2D54, Bethesda, MD 20892, USA.
authors.forename: Leland
authors.initials: L
authors.lastname: Krych
authors.affiliation: Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bldg. 10, Rm. 2D54, Bethesda, MD 20892, USA.
authors.forename: Zengyan
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bldg. 10, Rm. 2D54, Bethesda, MD 20892, USA. Electronic address: beebe@mail.nih.gov.
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Smith
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism; D001095:Arachidonic Acids / Q000378:metabolism*; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D015742:Propofol / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism; D012919:Social Behavior; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D063387:Cannabinoid Receptor Antagonists; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D051860:Fragile X Messenger Ribonucleoprotein 1; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D015742:Propofol; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D011963:Receptors, GABA-A; D000099252:Fatty Acid Amide Hydrolases; C578453:CNR1 protein, mouse; C497684:Fmr1 protein, mouse; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C103505:AM 251; C078814:anandamide
keywords: FAAH; Fmr1 KO mice; Fragile X syndrome; Memory; Passive avoidance; Propofol