| Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors. | |
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MedLine Citation:
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PMID: 20801430 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Paola Mascia; Marco Pistis; Zuzana Justinova; Leigh V Panlilio; Antonio Luchicchi; Salvatore Lecca; Maria Scherma; Walter Fratta; Paola Fadda; Chanel Barnes; Godfrey H Redhi; Sevil Yasar; Bernard Le Foll; Gianluigi Tanda; Daniele Piomelli; Steven R Goldberg |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Biological psychiatry Volume: 69 ISSN: 1873-2402 ISO Abbreviation: Biol. Psychiatry Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-03-14 Completed Date: 2011-07-01 Revised Date: 2012-04-04 |
Medline Journal Info:
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Nlm Unique ID: 0213264 Medline TA: Biol Psychiatry Country: United States |
Other Details:
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Languages: eng Pagination: 633-41 Citation Subset: IM |
Copyright Information:
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Published by Elsevier Inc. |
Affiliation:
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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. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Action Potentials
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drug effects Animals Behavior, Animal / drug effects Conditioning, Operant / drug effects Dopamine / metabolism Dose-Response Relationship, Drug Drug Interactions Enzyme Inhibitors / pharmacology Indoles / pharmacology Male Microdialysis / methods Neurons / drug effects Nicotine / administration & dosage* Nicotinic Agonists / administration & dosage* Nucleus Accumbens / drug effects, metabolism Oligosaccharides / pharmacology PPAR alpha / metabolism* Peroxisome Proliferators / pharmacology Pyrimidines / pharmacology Rats Rats, Sprague-Dawley Reinforcement (Psychology)* Reward* Saimiri Self Administration Ventral Tegmental Area / cytology |
| Grant Support | |
ID/Acronym/Agency:
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N01 DA059909/DA/NIDA NIH HHS; Z01 DA000001-23/DA/NIDA NIH HHS; Z01 DA000003-22/DA/NIDA NIH HHS; Z99 DA999999/DA/NIDA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Indoles; 0/Nicotinic Agonists; 0/Oligosaccharides; 0/PPAR alpha; 0/Peroxisome Proliferators; 0/Pyrimidines; 118414-82-7/L 663536; 128536-86-7/methyl oligobiosaminide; 50892-23-4/pirinixic acid; 54-11-5/Nicotine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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