title: Attenuating Nicotine Reinforcement and Relapse by Enhancing Endogenous Brain Levels of Kynurenic Acid in Rats and Squirrel Monkeys.
abstract: The currently available antismoking medications have limited efficacy and often fail to prevent relapse. Thus, there is a pressing need for newer, more effective treatment strategies. Recently, we demonstrated that enhancing endogenous levels of kynurenic acid (KYNA, a neuroinhibitory product of tryptophan metabolism) counteracts the rewarding effects of cannabinoids by acting as a negative allosteric modulator of α7 nicotinic receptors (α7nAChRs). As the effects of KYNA on cannabinoid reward involve nicotinic receptors, in the present study we used rat and squirrel monkey models of reward and relapse to examine the possibility that enhancing KYNA can counteract the effects of nicotine. To assess specificity, we also examined models of cocaine reward and relapse in monkeys. KYNA levels were enhanced by administering the kynurenine 3-monooxygenase (KMO) inhibitor, Ro 61-8048. Treatment with Ro 61-8048 decreased nicotine self-administration in rats and monkeys, but did not affect cocaine self-administration. In rats, Ro 61-8048 reduced the ability of nicotine to induce dopamine release in the nucleus accumbens shell, a brain area believed to underlie nicotine reward. Perhaps most importantly, Ro 61-8048 prevented relapse-like behavior when abstinent rats or monkeys were reexposed to nicotine and/or cues that had previously been associated with nicotine. Ro 61-8048 was also effective in monkey models of cocaine relapse. All of these effects of Ro 61-8048 in monkeys, but not in rats, were reversed by pretreatment with a positive allosteric modulator of α7nAChRs. These findings suggest that KMO inhibition may be a promising new approach for the treatment of nicotine addiction.
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Secci
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA.
authors.forename: Alessia
authors.initials: A
authors.lastname: Auber
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA.
authors.forename: Leigh V
authors.initials: LV
authors.lastname: Panlilio
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA.
authors.forename: Godfrey H
authors.initials: GH
authors.lastname: Redhi
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Thorndike
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Schindler
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarcz
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Justinova
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D007736:Kynurenic Acid / Q000378:metabolism*; D008297:Male; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects; D010671:Phenylurea Compounds / Q000494:pharmacology; D051381:Rats; D012008:Recurrence; D012054:Reinforcement, Psychology; D012453:Saimiri; D055502:Secondary Prevention; D012646:Self Administration; D013449:Sulfonamides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013844:Thiazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; D007555:Isoxazoles; D010671:Phenylurea Compounds; C110196:Ro 61-8048; D013449:Sulfonamides; D013844:Thiazoles; D009538:Nicotine; D007736:Kynurenic Acid; D003042:Cocaine; D004298:Dopamine