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.
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.
Scherma
Maria
M
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.
Panlilio
Leigh V
LV
Fadda
Paola
P
Fattore
Liana
L
Gamaleddin
Islam
I
Le Foll
Bernard
B
Justinová
Zuzana
Z
Mikics
Eva
E
Haller
Jozsef
J
Medalie
Julie
J
Stroik
Jessica
J
Barnes
Chanel
C
Yasar
Sevil
S
Tanda
Gianluigi
G
Piomelli
Daniele
D
Fratta
Walter
W
Goldberg
Steven R
SR
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
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