title: Brain Responses to Smoking Cues Differ Based on Nicotine Metabolism Rate.
abstract: Inherited differences in the rate of metabolism of nicotine, the addictive chemical in tobacco, affect smoking behavior and quitting success. The nicotine metabolite ratio (3'-hydroxycotinine/cotinine) is a reliable measure of nicotine clearance and a well-validated predictive biomarker of response to pharmacotherapy. To clarify the mechanisms underlying these associations, we investigated the neural responses to smoking cues in normal and slow nicotine metabolizers.
  
  
  
  Treatment-seeking smokers (N = 69; 30 slow metabolizers and 39 normal metabolizers) completed a visual cue reactivity task during functional magnetic resonance imaging on two separate occasions: once during smoking satiety and once after 24 hours of smoking abstinence.
  
  
  
  In whole-brain analysis, normal (compared with slow) metabolizers exhibited heightened abstinence-induced neural responses to smoking cues in the left caudate, left inferior frontal gyrus, and left frontal pole. These effects were more pronounced when extreme groups of slow and normal metabolizers were examined. Greater activation in the left caudate and left frontal pole was associated with abstinence-induced subjective cravings to smoke.
  
  
  
  Inherited differences in rate of nicotine elimination may drive neural responses to smoking cues during early abstinence, providing a plausible mechanism to explain differences in smoking behaviors and response to cessation treatment. Normal metabolizers may benefit from adjunctive behavioral smoking cessation treatments, such as cue exposure therapy.
authors.affiliation: Center for Interdisciplinary Research on Nicotine Addiction, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Mary
authors.initials: M
authors.lastname: Falcone
authors.affiliation: Center for Interdisciplinary Research on Nicotine Addiction, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Wen
authors.initials: W
authors.lastname: Cao
authors.affiliation: Center for Interdisciplinary Research on Nicotine Addiction, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Leah
authors.initials: L
authors.lastname: Bernardo
authors.affiliation: Campbell Family Mental Health Research Institute, University of Toronto, Toronto, Ontario, Canada; Centre for Addiction and Mental Health, and Departments of Psychiatry and Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
authors.affiliation: Center for Interdisciplinary Research on Nicotine Addiction, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: James
authors.initials: J
authors.lastname: Loughead
authors.affiliation: Center for Interdisciplinary Research on Nicotine Addiction, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: clerman@upenn.edu.
authors.forename: Caryn
authors.initials: C
authors.lastname: Lerman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D003367:Cotinine / Q000031:analogs & derivatives / Q000378:metabolism; D003463:Cues; D005260:Female; D059907:Functional Neuroimaging; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000378:metabolism*; D012463:Saliva / Q000378:metabolism; D012907:Smoking / Q000378:metabolism*; D055815:Young Adult
chemical_list: C001381:hydroxycotinine; D009538:Nicotine; D003367:Cotinine
keywords: Cue reactivity; Neuroimaging; Nicotine; Nicotine addiction; Nicotine metabolite ratio; Withdrawal