title: Effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats.
abstract: Manipulations of the endocannabinoid system could potentially produce therapeutic effects with minimal risk of adverse cannabis-like side effects. Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of the cannabinoid-receptor agonist, anandamide, and show promise for treating a wide range of disorders. However, their effects on learning and memory have not been fully characterized.
  
  
  
  We determined the effects of five structurally different FAAH inhibitors in an animal model of working memory known to be sensitive to impairment by delta-9 tetrahydrocannabinol (THC).
  
  
  
  A delayed nonmatching-to-position procedure was used in rats. Illuminated nosepoke holes were used to provide sample cues (left versus right) and record responses (correct versus incorrect) after delays ranging from 0 to 28 s. Various test drugs were given acutely up to two times per week before daily sessions.
  
  
  
  One FAAH inhibitor, AM3506 (3 mg/kg), decreased accuracy in the memory task. Four other FAAH inhibitors (URB597, URB694, PF-04457845, and ARN14633) and a monoacylglycerol lipase inhibitor (JZL184, which blocks the degradation of the endocannabinoid 2-arachidonoylglycerol) had no effect. Testing of AM3506 in combination with antagonists for receptors known to be affected by anandamide and other fatty acid amides indicated that the impairment induced by AM3506 was mediated by cannabinoid CB1 receptors, and not by alpha-type peroxisome proliferator-activated receptors (PPAR-alpha) or vanilloid transient receptor potential cation channels (TRPV1).
  
  
  
  FAAH inhibitors differ with respect to their potential for memory impairment, abuse liability, and probably other cannabis-like effects, and they should be evaluated individually for specific therapeutic and adverse effects.
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA. lpanlili@mail.nih.gov.
authors.forename: Leigh V
authors.initials: LV
authors.lastname: Panlilio
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Thorndike
authors.affiliation: Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
authors.forename: Spyros P
authors.initials: SP
authors.lastname: Nikas
authors.affiliation: MAKScientific, LLC, Boston, MA, USA.
authors.forename: Shakiru O
authors.initials: SO
authors.lastname: Alapafuja
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Bandiera
authors.affiliation: The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.|Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Center for Drug Discovery, Department of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.|Department of Anatomy and Neurobiology, University of California Irvine, Irvine, CA, USA.
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Justinova
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects*; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide
keywords: Delayed spatial matching; Endocannabinoids; FAAH inhibition; Monoacylglycerol lipase inhibition; Working memory