title: Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task.
abstract: Recent reports have demonstrated that disruption of CB(1) receptor signaling impairs extinction of learned responses in conditioned fear and Morris water maze paradigms. Here, we test the hypothesis that elevating brain levels of the endogenous cannabinoid anandamide through either genetic deletion or pharmacological inhibition of its primary catabolic enzyme fatty-acid amide hydrolase (FAAH) will potentiate extinction in a fixed platform water maze task. FAAH (-/-) mice and mice treated with the FAAH inhibitor OL-135, did not display any memory impairment or motor disruption, but did exhibit a significant increase in the rate of extinction. Unexpectedly, FAAH-compromised mice also exhibited a significant increase in acquisition rate. The CB(1) receptor antagonist SR141716 (rimonabant) when given alone had no effects on acquisition, but disrupted extinction. Additionally, SR141716 blocked the effects of OL-135 on both acquisition and extinction. Collectively, these results indicate that endogenous anandamide plays a facilitatory role in extinction through a CB(1) receptor mechanism of action. In contrast, the primary psychoactive constituent of marijuana, Delta(9)-tetrahydrocannabinol, failed to affect extinction rates, suggesting that FAAH is a more effective target than a direct acting CB(1) receptor agonist in facilitating extinction. More generally, these findings suggest that FAAH inhibition represents a promising pharmacological approach to treat psychopathologies hallmarked by an inability to extinguish maladaptive behaviors, such as post-traumatic stress syndrome and obsessive-compulsive disorder.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Varvel
authors.forename: Laura E
authors.initials: LE
authors.lastname: Wise
authors.forename: Floride
authors.initials: F
authors.lastname: Niyuhire
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D013759:Dronabinol / Q000494:pharmacology; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005260:Female; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009771:Obsessive-Compulsive Disorder / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077285:Rimonabant; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D013759:Dronabinol; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant; D000099252:Fatty Acid Amide Hydrolases; C495479:1-oxo-1-(5-(2-pyridyl)-2-yl)-7-phenylheptane; C078814:anandamide