title: In vivo interactions between α7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α: Implication for nicotine dependence.
abstract: Chronic tobacco use dramatically increases health burdens and financial costs. Limitations of current smoking cessation therapies indicate the need for improved molecular targets. The main addictive component of tobacco, nicotine, exerts its dependency effects via nicotinic acetylcholine receptors (nAChRs). Activation of the homomeric α7 nAChR reduces nicotine's rewarding properties in conditioned place preference (CPP) test and i.v. self-administration models, but the mechanism underlying these effects is unknown. Recently, the nuclear receptor peroxisome proliferator-activated receptor type-α (PPARα) has been implicated as a downstream signaling target of the α7 nAChR in ventral tegmental area dopamine cells. The present study investigated PPARα as a possible mediator of the effect of α7 nAChR activation in nicotine dependence. Our results demonstrate the PPARα antagonist GW6471 blocks actions of the α7 nAChR agonist PNU282987 on nicotine reward in an unbiased CPP test in male ICR adult mice. These findings suggests that α7 nAChR activation attenuates nicotine CPP in a PPARα-dependent manner. To evaluate PPARα activation in nicotine dependence we used the selective and potent PPARα agonist, WY-14643 and the clinically used PPARα activator, fenofibrate, in nicotine CPP and we observed attenuation of nicotine preference, but fenofibrate was less potent. We also studied PPARα in nicotine dependence by evaluating its activation in nicotine withdrawal. WY-14643 reversed nicotine withdrawal signs whereas fenofibrate had modest efficacy. This suggests that PPARα plays a role in nicotine reward and withdrawal and that further studies are warranted to elucidate its function in mediating the effects of α7 nAChRs in nicotine dependence.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States. Electronic address: jacksonab2@mymail.vcu.edu.
authors.forename: Asti
authors.initials: A
authors.lastname: Jackson
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States; Experimental Animals Breeding and Research Center, Faculty of Medicine, Uludag University, Bursa, Turkey.
authors.forename: Deniz
authors.initials: D
authors.lastname: Bagdas
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States.
authors.forename: Pretal P
authors.initials: PP
authors.lastname: Muldoon
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States.
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC, United States.
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
authors.affiliation: Substance Abuse Research Division, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 2761 East Jefferson Ave., Detroit, MI 48207, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Greenwald
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Miles
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States.
authors.forename: M Imad
authors.initials: MI
authors.lastname: Damaj
mesh_terms: D000779:Anesthetics, Local / Q000008:administration & dosage; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage; D003216:Conditioning, Operant / Q000187:drug effects; D004195:Disease Models, Animal; D011345:Fenofibrate / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy; D014029:Tobacco Use Disorder / Q000188:drug therapy*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D000779:Anesthetics, Local; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; C449302:GW 6471; D000960:Hypolipidemic Agents; D018722:Nicotinic Agonists; D010080:Oxazoles; C498513:PNU-282987; D047493:PPAR alpha; D011743:Pyrimidines; D064569:alpha7 Nicotinic Acetylcholine Receptor; D014443:Tyrosine; D009538:Nicotine; C006253:pirinixic acid; D003042:Cocaine; D011345:Fenofibrate
keywords: Behavioral pharmacology; Mice; Nicotine dependence