Neuroimaging Research Branch, National Institute on Drug Abuse (NIDA), Intramural Research Program, Baltimore, 21224, USA.
Genes Brain Behav. 2013 Jul;12(5):554-63. doi: 10.1111/gbb.12027. Epub 2013 Apr 11.
Nicotine and tonic dopamine (DA) levels [as inferred by catechol-O-methyl tranferase (COMT) Val158Met genotype] interact to affect prefrontal processing. Prefrontal cortical areas are involved in response to performance feedback, which is impaired in smokers. We investigated whether there is a nicotine × COMT genotype interaction in brain circuitry during performance feedback of a reward task. We scanned 23 healthy smokers (10 Val/Val homozygotes, 13 Met allele carriers) during two fMRI sessions while subjects were wearing a nicotine or placebo patch. A significant nicotine × COMT genotype interaction for BOLD signal during performance feedback in cortico-striatal areas was seen. Activation in these areas during the nicotine patch condition was greater in Val/Val homozygotes and reduced in Met allele carriers. During negative performance feedback, the change in activation in error detection areas such as anterior cingulate cortex (ACC)/superior frontal gyrus on nicotine compared to placebo was greater in Val/Val homozygotes compared to Met allele carriers. With transdermal nicotine administration, Val/Val homozygotes showed greater activation with performance feedback in the dorsal striatum, area associated with habitual responding. In response to negative feedback, Val/Val homozygotes had greater activation in error detection areas, including the ACC, suggesting increased sensitivity to loss with nicotine exposure. Although these results are preliminary due to small sample size, they suggest a possible neurobiological mechanism underlying the clinical observation that Val/Val homozygotes, presumably with elevated COMT activity compared to Met allele carriers and therefore reduced prefrontal DA levels, have poorer outcomes with nicotine replacement therapy.
尼古丁和基础多巴胺（DA）水平[由儿茶酚-O-甲基转移酶（COMT）Val158Met 基因型推断]相互作用，影响前额叶处理。前额皮质区域参与对绩效反馈的反应，而吸烟者的这种反应受损。我们研究了在奖励任务的绩效反馈过程中，大脑回路中是否存在尼古丁×COMT 基因型相互作用。我们在 23 名健康吸烟者（10 名 Val/Val 纯合子，13 名 Met 等位基因携带者）进行两次功能磁共振成像（fMRI）扫描，同时受试者佩戴尼古丁或安慰剂贴片。在皮质纹状体区域，我们观察到在反馈过程中大脑活动的显著的尼古丁×COMT 基因型相互作用。在尼古丁贴片条件下，Val/Val 纯合子的激活增加，而 Met 等位基因携带者的激活减少。在负面绩效反馈期间，与安慰剂相比，在尼古丁贴片条件下，前扣带回皮层（ACC）/额上回等错误检测区域的激活变化在 Val/Val 纯合子中比在 Met 等位基因携带者中更大。在经皮给予尼古丁后，Val/Val 纯合子在背侧纹状体（与习惯性反应相关的区域）的反馈中表现出更大的激活。对负面反馈的反应中，Val/Val 纯合子在错误检测区域（包括 ACC）中的激活更大，表明在尼古丁暴露下对损失的敏感性增加。尽管由于样本量小，这些结果初步，但它们提示了一种可能的神经生物学机制，即 Val/Val 纯合子与 Met 等位基因携带者相比，COMT 活性升高，因此前额叶 DA 水平降低，在尼古丁替代治疗中结果较差，这可能是临床观察的基础。
