Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University St, Room WB 214D, Montreal, QC, Canada H3A 2B4.
Neuroimage. 2012 May 1;60(4):2136-43. doi: 10.1016/j.neuroimage.2012.01.119. Epub 2012 Feb 3.
Smoking cues trigger craving for cigarettes and relapse. Nicotine metabolism, mediated by the enzyme CYP2A6, also influences smoking behavior. In this study, we investigated how nicotine metabolism and genetic variation in CYP2A6 influence the neural response to smoking cues in humans using functional magnetic resonance imaging (fMRI). We hypothesized that individuals with faster rates of nicotine metabolism would have stronger conditioned responses to smoking cues because of closer coupling in everyday life between exposure to cigarettes and surges in blood nicotine concentration. In contrast, individuals with reduced rates of metabolism, who have relatively constant nicotine blood levels throughout the day, should be less likely to develop conditioned responses to cues. We screened 169 smokers for their rate of nicotine metabolism and CYP2A6 genotype, and selected 31 smokers with the fastest and slowest rates for fMRI, matched for daily cigarette intake. We measured their neural response to visual smoking and non-smoking cues using fMRI. As predicted, fast metabolizers, by phenotype or genotype, had significantly greater responses to visual cigarette cues than slow metabolizers in the amygdala, hippocampus, striatum, insula, and cingulate cortex. These results support the theory that drug cues are conditioned stimuli, and explain why fast metabolizers who smoke have lower cessation rates. They also provide insight into how genetics can shape human vulnerability to addiction, and have implications for tailoring smoking cessation programs based on individual genetics.
吸烟线索会引发对香烟的渴望和复吸。尼古丁代谢，由酶 CYP2A6 介导，也会影响吸烟行为。在这项研究中，我们使用功能磁共振成像（fMRI）研究了尼古丁代谢和 CYP2A6 遗传变异如何影响人类对吸烟线索的神经反应。我们假设，由于日常生活中暴露于香烟和血液尼古丁浓度激增之间的紧密耦合，尼古丁代谢率较高的个体对吸烟线索的条件反应会更强。相比之下，代谢率较低的个体，其血液中的尼古丁水平在一天中相对稳定，因此不太可能对线索产生条件反应。我们对 169 名吸烟者进行了尼古丁代谢率和 CYP2A6 基因型筛选，并选择了代谢最快和最慢的 31 名吸烟者进行 fMRI 匹配，每天的吸烟量相同。我们使用 fMRI 测量了他们对视觉吸烟和非吸烟线索的神经反应。正如预测的那样，表型或基因型快速代谢者在杏仁核、海马体、纹状体、脑岛和扣带回皮层对视觉香烟线索的反应明显大于慢代谢者。这些结果支持了药物线索是条件刺激的理论，并解释了为什么吸烟的快速代谢者戒烟率较低。它们还提供了有关遗传如何塑造人类对成瘾的易感性的见解，并为根据个体遗传学量身定制戒烟计划提供了依据。
