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

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

doi:https://doi.org/10.1016/j.biopsych.2010.07.009

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

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

Research output: Contribution to journal › Article › Academic › peer-review

106 Citations (Scopus)

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.

Original language	English
Pages (from-to)	633-41
Number of pages	9
Journal	Biological Psychiatry
Volume	69
Issue number	7
DOIs	https://doi.org/10.1016/j.biopsych.2010.07.009
Publication status	Published - 1 Apr 2011
Externally published	Yes

Keywords

Action Potentials
Animals
Behavior, Animal
Conditioning, Operant
Dopamine
Dose-Response Relationship, Drug
Drug Interactions
Enzyme Inhibitors
Indoles
Journal Article
Male
Microdialysis
Neurons
Nicotine
Nicotinic Agonists
Nucleus Accumbens
Oligosaccharides
PPAR alpha
Peroxisome Proliferators
Pyrimidines
Rats
Rats, Sprague-Dawley
Reinforcement (Psychology)
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Reward
Saimiri
Self Administration
Ventral Tegmental Area

Access to Document

https://doi.org/10.1016/j.biopsych.2010.07.009

Cite this

Mascia, P., Pistis, M., Justinova, Z., Panlilio, L. V., Luchicchi, A., Lecca, S., Scherma, M., Fratta, W., Fadda, P., Barnes, C., Redhi, G. H., Yasar, S., Le Foll, B., Tanda, G., Piomelli, D., & Goldberg, S. R. (2011). Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors. Biological Psychiatry, 69(7), 633-41. https://doi.org/10.1016/j.biopsych.2010.07.009

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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.",

keywords = "Action Potentials, Animals, Behavior, Animal, Conditioning, Operant, Dopamine, Dose-Response Relationship, Drug, Drug Interactions, Enzyme Inhibitors, Indoles, Journal Article, Male, Microdialysis, Neurons, Nicotine, Nicotinic Agonists, Nucleus Accumbens, Oligosaccharides, PPAR alpha, Peroxisome Proliferators, Pyrimidines, Rats, Rats, Sprague-Dawley, Reinforcement (Psychology), Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Reward, Saimiri, Self Administration, Ventral Tegmental Area",

author = "Paola Mascia and Marco Pistis and Zuzana Justinova and Panlilio, {Leigh V} and Antonio Luchicchi and Salvatore Lecca and Maria Scherma and Walter Fratta and Paola Fadda and Chanel Barnes and Redhi, {Godfrey H} and Sevil Yasar and {Le Foll}, Bernard and Gianluigi Tanda and Daniele Piomelli and Goldberg, {Steven R}",

year = "2011",

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day = "1",

doi = "https://doi.org/10.1016/j.biopsych.2010.07.009",

language = "English",

volume = "69",

pages = "633--41",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier USA",

number = "7",

}

Mascia, P, Pistis, M, Justinova, Z, Panlilio, LV, Luchicchi, A, Lecca, S, Scherma, M, Fratta, W, Fadda, P, Barnes, C, Redhi, GH, Yasar, S, Le Foll, B, Tanda, G, Piomelli, D & Goldberg, SR 2011, 'Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors', Biological Psychiatry, vol. 69, no. 7, pp. 633-41. https://doi.org/10.1016/j.biopsych.2010.07.009

TY - JOUR

T1 - Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors

AU - Mascia, Paola

AU - Pistis, Marco

AU - Justinova, Zuzana

AU - Panlilio, Leigh V

AU - Luchicchi, Antonio

AU - Lecca, Salvatore

AU - Scherma, Maria

AU - Fratta, Walter

AU - Fadda, Paola

AU - Barnes, Chanel

AU - Redhi, Godfrey H

AU - Yasar, Sevil

AU - Le Foll, Bernard

AU - Tanda, Gianluigi

AU - Piomelli, Daniele

AU - Goldberg, Steven R

PY - 2011/4/1

Y1 - 2011/4/1

N2 - 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.

AB - 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.

KW - Action Potentials

KW - Animals

KW - Behavior, Animal

KW - Conditioning, Operant

KW - Dopamine

KW - Dose-Response Relationship, Drug

KW - Drug Interactions

KW - Enzyme Inhibitors

KW - Indoles

KW - Journal Article

KW - Male

KW - Microdialysis

KW - Neurons

KW - Nicotine

KW - Nicotinic Agonists

KW - Nucleus Accumbens

KW - Oligosaccharides

KW - PPAR alpha

KW - Peroxisome Proliferators

KW - Pyrimidines

KW - Rats

KW - Rats, Sprague-Dawley

KW - Reinforcement (Psychology)

KW - Research Support, N.I.H., Intramural

KW - Research Support, Non-U.S. Gov't

KW - Reward

KW - Saimiri

KW - Self Administration

KW - Ventral Tegmental Area

U2 - https://doi.org/10.1016/j.biopsych.2010.07.009

DO - https://doi.org/10.1016/j.biopsych.2010.07.009

M3 - Article

C2 - 20801430

SN - 0006-3223

VL - 69

SP - 633

EP - 641

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 7

ER -