Department of Psychology, Idaho State University, Pocatello, ID;
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;
Nicotine Tob Res. 2014 Jul;16(7):939-47. doi: 10.1093/ntr/ntu010. Epub 2014 Mar 22.
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.
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.
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.
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.
对吸烟线索的反应性是吸烟动机的一个重要因素，与多巴胺受体 4 可变数目串联重复（DRD4 外显子 III VNTR）多态性有关。然而，与之相关的神经机制知之甚少。
非治疗寻求的白种烟民在两次单独的功能磁共振成像扫描中完成了一夜的禁欲，并观看了吸烟和中性线索，同时佩戴尼古丁或安慰剂贴片（按顺序随机化），并对 DRD4 VNTR 进行了基因分型。我们对混合效应重复测量方差分析（组内因素：尼古丁或安慰剂贴片；组间因素：DRD4 长[L：至少有一个≥7 个重复的拷贝]或短[S：2 个拷贝≤6 个重复]基因型）进行了 6 个事先确定的感兴趣区域。
与中性线索相比，吸烟线索在尼古丁替代期间诱发双侧腹侧纹状体和左侧杏仁核的更大活动，而在尼古丁剥夺期间这些区域的去激活。在左侧杏仁核中观察到贴片×DRD4 相互作用，该区域与奖赏强化和复发风险有关，因此 S 等位基因携带者在活性贴片上的激活大于安慰剂贴片。
与奖赏突显相关的大脑系统可能在戒烟的第一步中用于尼古丁替代的剂量下被启动和过度反应，并且在 DRD4 S 而非 DRD4 L 携带者的尼古丁戒断期间可能被抑制。这些发现与这些区域在药物强化中的作用一致，并表明在与吸烟刺激相关的激励性突显与 DRD4 基因型的关联中，尼古丁替代对杏仁核激活的影响存在差异。
