2. Academic Validation
  3. Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors

Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors

  • Biol Psychiatry. 2011 Apr 1;69(7):633-41. doi: 10.1016/j.biopsych.2010.07.009.
Paola Mascia 1,  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
Affiliations

Affiliation

  • 1 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.
PMID: 20801430 DOI: 10.1016/j.biopsych.2010.07.009
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.

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