title: Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors.
abstract: BACKGROUND
  Recent findings indicate that inhibitors of fatty acid amide hydrolase (FAAH) counteract the rewarding effects of nicotine in rats. Inhibition of FAAH increases levels of several endogenous substances in the brain, including the endocannabinoid anandamide and the noncannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide, which are ligands for alpha-type peroxisome proliferator-activated nuclear receptors (PPAR-α). Here, we evaluated whether directly acting PPAR-α agonists can modulate reward-related effects of nicotine.
  
  
  METHODS
  We combined behavioral, neurochemical, and electrophysiological approaches to evaluate effects of the PPAR-α agonists [[4-Chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]acetic acid (WY14643) and methyl oleoylethanolamide (methOEA; a long-lasting form of OEA) on 1) nicotine self-administration in rats and squirrel monkeys; 2) reinstatement of nicotine-seeking behavior in rats and monkeys; 3) nicotine discrimination in rats; 4) nicotine-induced electrophysiological activity of ventral tegmental area dopamine neurons in anesthetized rats; and 5) nicotine-induced elevation of dopamine levels in the nucleus accumbens shell of freely moving rats.
  
  
  RESULTS
  The PPAR-α agonists dose-dependently decreased nicotine self-administration and nicotine-induced reinstatement in rats and monkeys but did not alter food- or cocaine-reinforced operant behavior or the interoceptive effects of nicotine. The PPAR-α agonists also dose-dependently decreased nicotine-induced excitation of dopamine neurons in the ventral tegmental area and nicotine-induced elevations of dopamine levels in the nucleus accumbens shell of rats. The ability of WY14643 and methOEA to counteract the behavioral, electrophysiological, and neurochemical effects of nicotine was reversed by the PPAR-α antagonist 1-[(4-Chlorophenyl)methyl]-3-[(1,1-dimethylethyl)thio]-a,a-dimethyl-5-(1-methylethyl)-1H-Indole-2-propanoic acid (MK886).
  
  
  CONCLUSIONS
  These findings indicate that PPAR-α might provide a valuable new target for antismoking medications.
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Medications Discovery Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Mascia
authors.forename: Marco
authors.initials: M
authors.lastname: Pistis
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Justinova
authors.forename: Leigh V
authors.initials: LV
authors.lastname: Panlilio
authors.forename: Antonio
authors.initials: A
authors.lastname: Luchicchi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Lecca
authors.forename: Maria
authors.initials: M
authors.lastname: Scherma
authors.forename: Walter
authors.initials: W
authors.lastname: Fratta
authors.forename: Paola
authors.initials: P
authors.lastname: Fadda
authors.forename: Chanel
authors.initials: C
authors.lastname: Barnes
authors.forename: Godfrey H
authors.initials: GH
authors.lastname: Redhi
authors.forename: Sevil
authors.initials: S
authors.lastname: Yasar
authors.forename: Bernard
authors.initials: B
authors.lastname: Le Foll
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Tanda
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D017551:Microdialysis / Q000379:methods; D009474:Neurons / Q000187:drug effects; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D009844:Oligosaccharides / Q000494:pharmacology; D047493:PPAR alpha / Q000378:metabolism*; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012201:Reward; D012453:Saimiri; D012646:Self Administration; D017557:Ventral Tegmental Area / Q000166:cytology; D002722:Chlorobenzenes
chemical_list: D004298:Dopamine; D004791:Enzyme Inhibitors; D007211:Indoles; D009538:Nicotine; D018722:Nicotinic Agonists; D009844:Oligosaccharides; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; C060893:MK-886; D002722:Chlorobenzenes; C064839:methyl oligobiosaminide; C006253:pirinixic acid
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