title: Novel use of a lipid-lowering fibrate medication to prevent nicotine reward and relapse: preclinical findings.
abstract: Experimental drugs that activate α-type peroxisome proliferator-activated receptors (PPARα) have recently been shown to reduce the rewarding effects of nicotine in animals, but these drugs have not been approved for human use. The fibrates are a class of PPARα-activating medications that are widely prescribed to improve lipid profiles and prevent cardiovascular disease, but these drugs have not been tested in animal models of nicotine reward. Here, we examine the effects of clofibrate, a representative of the fibrate class, on reward-related behavioral, electrophysiological, and neurochemical effects of nicotine in rats and squirrel monkeys. Clofibrate prevented the acquisition of nicotine-taking behavior in naive animals, substantially decreased nicotine taking in experienced animals, and counteracted the relapse-inducing effects of re-exposure to nicotine or nicotine-associated cues after a period of abstinence. In the central nervous system, clofibrate blocked nicotine's effects on neuronal firing in the ventral tegmental area and on dopamine release in the nucleus accumbens shell. All of these results suggest that fibrate medications might promote smoking cessation. The fact that fibrates are already approved for human use could expedite clinical trials and subsequent implementation of fibrates as a treatment for tobacco dependence, especially in smokers with abnormal lipid profiles.
authors.affiliation: Intramural Research Program, Preclinical Pharmacology Section, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Leigh V
authors.initials: LV
authors.lastname: Panlilio
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Justinova
authors.forename: Paola
authors.initials: P
authors.lastname: Mascia
authors.forename: Marco
authors.initials: M
authors.lastname: Pistis
authors.forename: Antonio
authors.initials: A
authors.lastname: Luchicchi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Lecca
authors.forename: Chanel
authors.initials: C
authors.lastname: Barnes
authors.forename: Godfrey H
authors.initials: GH
authors.lastname: Redhi
authors.forename: Jordan
authors.initials: J
authors.lastname: Adair
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Heishman
authors.forename: Sevil
authors.initials: S
authors.lastname: Yasar
authors.forename: Mano
authors.initials: M
authors.lastname: Aliczki
authors.forename: Jozsef
authors.initials: J
authors.lastname: Haller
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002994:Clofibrate / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000523:psychology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000502:physiology; D009538:Nicotine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D012453:Saimiri; D055502:Secondary Prevention; D012646:Self Administration; D014029:Tobacco Use Disorder / Q000188:drug therapy; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology; D002722:Chlorobenzenes
chemical_list: D002994:Clofibrate; D004298:Dopamine; D000960:Hypolipidemic Agents; D007211:Indoles; D009538:Nicotine; D047493:PPAR alpha; C060893:MK-886; D002722:Chlorobenzenes