title: Inhibition of anandamide hydrolysis by cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester (URB597) reverses abuse-related behavioral and neurochemical effects of nicotine in rats.
abstract: Emerging evidence suggests that the rewarding, abuse-related effects of nicotine are modulated by the endocannabinoid system of the brain. For example, pharmacological blockade or genetic deletion of cannabinoid CB(1) receptors can reduce or eliminate many abuse-related behavioral and neurochemical effects of nicotine. Furthermore, doses of Delta(9)-tetrahydrocannabinol and nicotine that are ineffective when given alone can induce conditioned place preference when given together. These previous studies have used systemically administered CB(1) receptor agonists and antagonists and gene deletion techniques, which affect cannabinoid CB(1) receptors throughout the brain. A more functionally selective way to alter endocannabinoid activity is to inhibit fatty acid amide hydrolase (FAAH), thereby magnifying and prolonging the effects of the endocannabinoid anandamide only when and where it is synthesized and released on demand. Here, we combined behavioral and neurochemical approaches to evaluate whether the FAAH inhibitor URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) could alter the abuse-related effects of nicotine in rats. We found that URB597, at a dose (0.3 mg/kg) that had no behavioral effects by itself, prevented development of nicotine-induced conditioned place preference (CPP) and acquisition of nicotine self-administration. URB597 also reduced nicotine-induced reinstatement in both CPP and self-administration models of relapse. Furthermore, in vivo microdialysis showed that URB597 reduced nicotine-induced dopamine elevations in the nucleus accumbens shell, the terminal area of the brain's mesolimbic reward system. These findings suggest that FAAH inhibition can counteract the addictive properties of nicotine and that FAAH may serve as a new target for development of medications for treatment of tobacco dependence.
authors: Preclinical Pharmacology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224, USA.
authors: Maria
authors: M
authors: Scherma
authors: Leigh V
authors: LV
authors: Panlilio
authors: Paola
authors: P
authors: Fadda
authors: Liana
authors: L
authors: Fattore
authors: Islam
authors: I
authors: Gamaleddin
authors: Bernard
authors: B
authors: Le Foll
authors: Zuzana
authors: Z
authors: Justinová
authors: Eva
authors: E
authors: Mikics
authors: Jozsef
authors: J
authors: Haller
authors: Julie
authors: J
authors: Medalie
authors: Jessica
authors: J
authors: Stroik
authors: Chanel
authors: C
authors: Barnes
authors: Sevil
authors: S
authors: Yasar
authors: Gianluigi
authors: G
authors: Tanda
authors: Daniele
authors: D
authors: Piomelli
authors: Walter
authors: W
authors: Fratta
authors: Steven R
authors: SR
authors: Goldberg
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects*; D004298:Dopamine / Q000032:analysis*; D063388:Endocannabinoids; D006868:Hydrolysis; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000737:chemistry / Q000187:drug effects*; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D012201:Reward; D012646:Self Administration; D014029:Tobacco Use Disorder / Q000188:drug therapy* / Q000201:enzymology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D002219:Carbamates; D004298:Dopamine; D063388:Endocannabinoids; D009538:Nicotine; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C078814:anandamide