title: The anandamide transport inhibitor AM404 reduces the rewarding effects of nicotine and nicotine-induced dopamine elevations in the nucleus accumbens shell in rats.
abstract: OBJECTIVE
  The fatty acid amide hydrolase inhibitor URB597 can reverse the abuse-related behavioural and neurochemical effects of nicotine in rats. Fatty acid amide hydrolase inhibitors block the degradation (and thereby magnify and prolong the actions) of the endocannabinoid anandamide (AEA), and also the non-cannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). OEA and PEA are endogenous ligands for peroxisome proliferator-activated receptors alpha (PPAR-α). Since recent evidence indicates that PPAR-α can modulate nicotine reward, it is unclear whether AEA plays a role in the effects of URB597 on nicotine reward.
  
  
  METHODS
  A way to selectively increase endogenous levels of AEA without altering OEA or PEA levels is to inhibit AEA uptake into cells by administering the AEA transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404). To clarify AEA's role in nicotine reward, we investigated the effect of AM404 on conditioned place preference (CPP), reinstatement of abolished CPP, locomotor suppression and anxiolysis in an open field, and dopamine elevations in the nucleus accumbens shell induced by nicotine in Sprague-Dawley rats.
  
  
  RESULTS
  AM404 prevented the development of nicotine-induced CPP and impeded nicotine-induced reinstatement of the abolished CPP. Furthermore, AM404 reduced nicotine-induced increases in dopamine levels in the nucleus accumbens shell, the terminal area of the brain's mesolimbic reward system. AM404 did not alter the locomotor suppressive or anxiolytic effect of nicotine.
  
  
  CONCLUSIONS
  These findings suggest that AEA transport inhibition can counteract the addictive effects of nicotine and that AEA transport may serve as a new target for development of medications for treatment of tobacco dependence.
  
  
  BACKGROUND
  This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Scherma
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Justinová
authors.forename: Claudio
authors.initials: C
authors.lastname: Zanettini
authors.forename: Leigh V
authors.initials: LV
authors.lastname: Panlilio
authors.forename: Paola
authors.initials: P
authors.lastname: Mascia
authors.forename: Paola
authors.initials: P
authors.lastname: Fadda
authors.forename: Walter
authors.initials: W
authors.lastname: Fratta
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.forename: Subramanian K
authors.initials: SK
authors.lastname: Vadivel
authors.forename: Islam
authors.initials: I
authors.lastname: Gamaleddin
authors.forename: Bernard
authors.initials: B
authors.lastname: Le Foll
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use*; D016739:Behavior, Addictive / Q000188:drug therapy* / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D003213:Conditioning, Psychological / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D013759:Dronabinol / Q000494:pharmacology; D063388:Endocannabinoids; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology; D053284:Polyunsaturated Alkamides / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D018722:Nicotinic Agonists; D053284:Polyunsaturated Alkamides; D009538:Nicotine; D013759:Dronabinol; C078814:anandamide; D004298:Dopamine; C107594:N-(4-hydroxyphenyl)arachidonylamide