Research Assistant Professor of Neuroscience, Addiction Treatment Research Center, Department of Psychiatry, University of Pennsylvania School of Medicine, 3900 Chestnut Street, Philadelphia, PA 19104, USA.
Addict Biol. 2011 Apr;16(2):308-22. doi: 10.1111/j.1369-1600.2010.00277.x. Epub 2011 Feb 8.
Previously we demonstrated profound effects of dopamine transporter (DAT) SLC6A3 genotype on limbic responses to smoking cues (SCs). Probands carrying at least one copy of the 9-repeat allele (9-repeat carriers) had greater neural responses to SCs in the anatomically interconnected rostral ventral striatum/medial orbitofrontal cortex (VS/mOFC), compared with homozygotes for the 10-repeat allele (10/10-repeats). To test the reliability of the initial findings, we examined perfusion functional magnetic resonance images acquired during SC exposure in a new cohort of smokers (N=26) who were genotyped for the SLC6A3 polymorphism. In smokers overall, activity was enhanced in the VS/mOFC (t=3.77). Contrasts between allelic groups revealed that 9-repeat carriers had a greater response to SCs in the VS (t=3.12) and mOFC (t=3.19). In separate groups, 9-repeat carriers showed increased activity in the VS (t=5.47) and mOFC (T=4.96), while no increases were observed in 10-repeats. Subjective reports of craving correlated with increased activity in reward-related structures including the extended amygdala, insula and post-central gyrus, and decreased activity in the dorsolateral prefrontal cortex, and were DAT-genotype dependent (r=0.63-0.96). In secondary analyses, we found that The Fagerström Test for Nicotine Dependence scores correlated with enhanced SC-induced perfusion in 10/10-repeats in the insula, mOFC, medial temporal and superior frontal gyri (r=0.50-0.82), while correlations were absent in 9-repeat carriers. Despite heterogeneity introduced by a host of factors, including variance in other genes involved in smoking behavior, we confirm that DAT genotype predicts the direction and location of neural responses to SCs.
先前，我们发现多巴胺转运体（DAT）SLC6A3 基因多态性对吸烟线索（SCs）引起的边缘反应有显著影响。携带至少一个 9 重复等位基因（9 重复携带者）的先证者与 10 重复等位基因（10/10 重复）纯合子相比，对 SCs 在解剖上相互连接的腹侧纹状体/内侧眶额皮层（VS/mOFC）的神经反应更大。为了检验最初发现的可靠性，我们在一组新的吸烟人群（N=26）中检查了 SC 暴露期间获得的灌注功能磁共振成像，这些人都进行了 SLC6A3 多态性的基因分型。在总体吸烟者中，VS/mOFC 的活动增强（t=3.77）。等位基因组之间的对比表明，9 重复携带者对 SC 在 VS（t=3.12）和 mOFC（t=3.19）的反应更大。在单独的组中，9 重复携带者在 VS（t=5.47）和 mOFC（T=4.96）中显示出活动增加，而 10 重复则没有增加。对渴望的主观报告与包括扩展杏仁核、岛叶和后中央回在内的奖励相关结构的活性增加相关，与背外侧前额叶皮层的活性降低相关，并且与 DAT 基因型相关（r=0.63-0.96）。在次要分析中，我们发现尼古丁依赖 Fagerström 测试评分与 10/10 重复的岛叶、mOFC、内侧颞叶和额上回中 SC 诱导的灌注增强相关（r=0.50-0.82），而在 9 重复携带者中则不存在相关性。尽管存在许多因素（包括涉及吸烟行为的其他基因的变异）引起的异质性，但我们确认 DAT 基因型预测了对 SC 的神经反应的方向和位置。
