title: Endocannabinoid regulation of acute and protracted nicotine withdrawal: effect of FAAH inhibition.
abstract: Evidence shows that the endocannabinoid system modulates the addictive properties of nicotine. In the present study, we hypothesized that spontaneous withdrawal resulting from removal of chronically implanted transdermal nicotine patches is regulated by the endocannabinoid system. A 7-day nicotine dependence procedure (5.2 mg/rat/day) elicited occurrence of reliable nicotine abstinence symptoms in Wistar rats. Somatic and affective withdrawal signs were observed at 16 and 34 hours following removal of nicotine patches, respectively. Further behavioral manifestations including decrease in locomotor activity and increased weight gain also occurred during withdrawal. Expression of spontaneous nicotine withdrawal was accompanied by fluctuation in levels of the endocannabinoid anandamide (AEA) in several brain structures including the amygdala, the hippocampus, the hypothalamus and the prefrontal cortex. Conversely, levels of 2-arachidonoyl-sn-glycerol were not significantly altered. Pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for the intracellular degradation of AEA, by URB597 (0.1 and 0.3 mg/kg, i.p.), reduced withdrawal-induced anxiety as assessed by the elevated plus maze test and the shock-probe defensive burying paradigm, but did not prevent the occurrence of somatic signs. Together, the results indicate that pharmacological strategies aimed at enhancing endocannabinoid signaling may offer therapeutic advantages to treat the negative affective state produced by nicotine withdrawal, which is critical for the maintenance of tobacco use.
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy. andrea.cippitelli@unicam.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Cippitelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Astarita
authors.forename: Andrea
authors.initials: A
authors.lastname: Duranti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Caprioli
authors.forename: Massimo
authors.initials: M
authors.lastname: Ubaldi
authors.forename: Serena
authors.initials: S
authors.lastname: Stopponi
authors.forename: Marsida
authors.initials: M
authors.lastname: Kallupi
authors.forename: Gianni
authors.initials: G
authors.lastname: Sagratini
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodrìguez de Fonseca
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccocioppo
mesh_terms: D000208:Acute Disease; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000097:blood / Q000150:complications / Q000503:physiopathology; D001095:Arachidonic Acids / Q000378:metabolism; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000473:pathology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology; D003367:Cotinine / Q000097:blood; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D020007:Implants, Experimental; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009538:Nicotine / Q000097:blood; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000150:complications / Q000201:enzymology* / Q000503:physiopathology; D061485:Tobacco Use Cessation Devices; D015430:Weight Gain / Q000187:drug effects; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D003367:Cotinine; D063388:Endocannabinoids; D005989:Glycerides; D009538:Nicotine; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C094503:glyceryl 2-arachidonate; C078814:anandamide