Xiaomeng Xu1, Uraina S Clark2, Sean P David3, Richard C Mulligan4, Valerie S Knopik5, John McGeary6, James MacKillop7, Jeanne McCaffery8, Raymond S Niaura9, Lawrence H Sweet10. 1. Department of Psychology, Idaho State University, Pocatello, ID; mona.xu@gmail.com. 2. Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI; Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY; 3. Division of General Medical Disciplines, Department of Medicine, Stanford University School of Medicine, Population Health Sciences Building, Palo Alto, CA; Center for Health Sciences, Biosciences Division, SRI International, Menlo Park, CA; Department of Family Medicine, Warren Alpert Medical School of Brown University, Pawtucket, RI; 4. Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI; Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO; 5. Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI; Division of Behavioral Genetics, Rhode Island Hospital, Bradley Hasbro Children's Research Center, Providence, RI; 6. Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI; Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI; Division of Behavioral Genetics, Rhode Island Hospital, Bradley Hasbro Children's Research Center, Providence, RI; Providence Veterans Affairs Medical Center, Providence, RI; 7. Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI; Department of Psychology, University of Georgia, Athens, GA; 8. Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI; Weight Control and Diabetes Research Center, Miriam Hospital, Providence, RI; 9. LEGACY, Schroeder Institute for Tobacco Research and Policy Studies, Washington, DC. 10. Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI; Department of Psychology, University of Georgia, Athens, GA;
Abstract
INTRODUCTION: Reactivity to smoking cues is an important factor in the motivation to smoke and has been associated with the dopamine receptor 4 variable number tandem repeat (DRD4 exon III VNTR) polymorphism. However, little is known about the associated neural mechanisms. METHODS: Non-treatment-seeking Caucasian smokers completed overnight abstinence and viewed smoking and neutral cues during 2 separate functional magnetic resonance imaging scans while wearing either a nicotine or placebo patch (order randomized) and were genotyped for the DRD4 VNTR. We conducted mixed-effects repeated-measures analyses of variance (within-subject factor: nicotine or placebo patch; between-subject factor: DRD4 long [L: ≥ 1 copy of ≥ 7 repeats] or short [S: 2 copies ≤ 6 repeats] genotype) of 6 a priori regions of interest. RESULTS: Relative to neutral cues, smoking cues elicited greater activity in bilateral ventral striatum and left amygdala during nicotine replacement and deactivation in these regions during nicotine deprivation. A patch × DRD4 interaction was observed in the left amygdala, an area associated with appetitive reinforcement and relapse risk, such that S allele carriers demonstrated greater activation on active patch than on placebo patch. CONCLUSIONS: Brain systems associated with reward salience may become primed and overreactive at nicotine replacement doses intended for the first step of smoking cessation and may become inhibited during nicotine withdrawal in DRD4 S but not in DRD4 L carriers. These findings are consistent with the role of these regions in drug reinforcement and suggest a differential influence of nicotine replacement on amygdala activation in the association of incentive salience with smoking stimuli across DRD4 genotypes.
RCT Entities:
INTRODUCTION: Reactivity to smoking cues is an important factor in the motivation to smoke and has been associated with the dopamine receptor 4 variable number tandem repeat (DRD4 exon III VNTR) polymorphism. However, little is known about the associated neural mechanisms. METHODS: Non-treatment-seeking Caucasian smokers completed overnight abstinence and viewed smoking and neutral cues during 2 separate functional magnetic resonance imaging scans while wearing either a nicotine or placebo patch (order randomized) and were genotyped for the DRD4 VNTR. We conducted mixed-effects repeated-measures analyses of variance (within-subject factor: nicotine or placebo patch; between-subject factor: DRD4 long [L: ≥ 1 copy of ≥ 7 repeats] or short [S: 2 copies ≤ 6 repeats] genotype) of 6 a priori regions of interest. RESULTS: Relative to neutral cues, smoking cues elicited greater activity in bilateral ventral striatum and left amygdala during nicotine replacement and deactivation in these regions during nicotine deprivation. A patch × DRD4 interaction was observed in the left amygdala, an area associated with appetitive reinforcement and relapse risk, such that S allele carriers demonstrated greater activation on active patch than on placebo patch. CONCLUSIONS: Brain systems associated with reward salience may become primed and overreactive at nicotine replacement doses intended for the first step of smoking cessation and may become inhibited during nicotine withdrawal in DRD4 S but not in DRD4 L carriers. These findings are consistent with the role of these regions in drug reinforcement and suggest a differential influence of nicotine replacement on amygdala activation in the association of incentive salience with smoking stimuli across DRD4 genotypes.
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