title: Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse.
abstract: Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors; (2) shifted nicotine self-administration dose-response functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell--consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement.
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, USA.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Justinova
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, USA.
authors.forename: Leigh V
authors.initials: LV
authors.lastname: Panlilio
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA, USA.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Moreno-Sanz
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, USA.
authors.forename: Godfrey H
authors.initials: GH
authors.lastname: Redhi
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, USA.
authors.forename: Alessia
authors.initials: A
authors.lastname: Auber
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Secci
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Mascia
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Bandiera
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Rosalia
authors.initials: R
authors.lastname: Bertorelli
authors.affiliation: Division of Clinical Research, National Institute of Allergy and Infectious Diseases, NIH, DHHS, Frederick, MD, USA.
authors.forename: Svetlana I
authors.initials: SI
authors.lastname: Chefer
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, USA.
authors.forename: Chanel
authors.initials: C
authors.lastname: Barnes
authors.affiliation: Department of Medicine, Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Sevil
authors.initials: S
authors.lastname: Yasar
authors.affiliation: 1] Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA, USA [2] Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.
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, NIH, DHHS, Baltimore, MD, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002219:Carbamates / Q000494:pharmacology*; D003463:Cues; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects; D005108:Extinction, Psychological / Q000187:drug effects; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023421:Models, Animal; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D012201:Reward; D012453:Saimiri; D012646:Self Administration; D013997:Time Factors
chemical_list: D001549:Benzamides; D001713:Biphenyl Compounds; D002219:Carbamates; D018722:Nicotinic Agonists; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C555899:cyclohexyl carbonic acid 3'-carbamoyl-3-yl ester; D009538:Nicotine; D006899:Mixed Function Oxygenases; C019081:fatty acid alpha-hydroxylase; D004298:Dopamine