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.
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