Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors.
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.
Mascia
Paola
P
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.
Pistis
Marco
M
Justinova
Zuzana
Z
Panlilio
Leigh V
LV
Luchicchi
Antonio
A
Lecca
Salvatore
S
Scherma
Maria
M
Fratta
Walter
W
Fadda
Paola
P
Barnes
Chanel
C
Redhi
Godfrey H
GH
Yasar
Sevil
S
Le Foll
Bernard
B
Tanda
Gianluigi
G
Piomelli
Daniele
D
Goldberg
Steven R
SR
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
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
Behav Pharmacol. 2002 Sep;13(5-6):451-63
12394421
J Neurobiol. 2002 Dec;53(4):606-17
12436424
Exp Neurol. 2010 Jul;224(1):48-55
20353771
J Pharmacol Exp Ther. 2006 Aug;318(2):563-70
16702440
Handb Exp Pharmacol. 2009;(192):295-333
19184654
Psychopharmacology (Berl). 2008 Oct;200(3):357-65
18587561
J Neurosci Methods. 1981 Jun;4(1):1-32
7253697
Neuropsychopharmacology. 2007 Mar;32(3):646-57
16738542
Brain Res. 1994 Aug 8;653(1-2):278-84
7982062
Br J Pharmacol. 2007 Nov;152(5):576-82
17704824
Psychopharmacology (Berl). 2003 Sep;169(2):135-40
12827345
Neuroscience. 2004;123(1):131-45
14667448
Psychopharmacology (Berl). 2009 Sep;205(4):613-24
19484221
J Pharmacol Exp Ther. 2005 Apr;313(1):352-8
15579492
Learn Mem. 2009 Apr 29;16(5):332-7
19403796
J Neurosci. 2003 Jul 16;23(15):6264-71
12867511
J Pharmacol Exp Ther. 2008 Nov;327(2):482-90
18725543
Nature. 2003 Sep 4;425(6953):90-3
12955147
Synapse. 1994 Jan;16(1):36-44
8134899
Biol Psychiatry. 2008 Dec 1;64(11):930-7
18814866
J Neurosci. 2007 May 23;27(21):5615-20
17522306
Pharmacol Biochem Behav. 1994 Jul;48(3):817-20
7938142
Neuropsychopharmacology. 2005 Apr;30(4):720-30
15562293
J Neurosci. 2005 Apr 6;25(14):3712-23
15814802
Psychopharmacology (Berl). 2006 Oct;188(2):252-7
16932923
Neuroreport. 2004 Sep 15;15(13):2139-43
15486497
J Neurosci. 1984 Nov;4(11):2877-90
6150071
Proc Natl Acad Sci U S A. 2009 May 12;106(19):8027-31
19416833
Biol Psychiatry. 2010 Aug 1;68(3):256-64
20570248
J Neurosci Methods. 1980 Dec;3(2):129-49
6110810
Eur J Pharmacol. 2006 Jul 1;540(1-3):96-106
16730696
Neuropharmacology. 2008 Feb;54(2):438-44
18054052
Curr Med Chem. 2002 Mar;9(6):663-74
11945130
Neuroreport. 1994 Dec 20;5(18):2481-5
7696585
J Neurosci. 2005 Oct 26;25(43):9836-49
16251431
Brain Res. 2007 Mar 2;1135(1):77-84
17196944
J Pharmacol Exp Ther. 1973 Jul;186(1):18-30
4198773
Cell Mol Life Sci. 2005 Mar;62(6):708-16
15770421
Pharmacol Biochem Behav. 2004 Nov;79(3):507-13
15582022
Science. 2004 Mar 26;303(5666):2040-2
15044807
J Neurosci. 2008 Dec 17;28(51):13985-94
19091987
Nature. 1996 Jul 18;382(6588):255-7
8717040
J Neurochem. 1998 Apr;70(4):1366-75
9523552