Perkins Kenneth A, Lerman Caryn, Coddington Sarah, Jetton Christopher, Karelitz Joshua L, Wilson Annette, Jennings J Richard, Ferrell Robert, Bergen Andrew W, Benowitz Neal L
Department of Psychiatry, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Behav Pharmacol. 2008 Sep;19(5-6):630-40. doi: 10.1097/FBP.0b013e32830c3621.
Genetic variation may influence initial sensitivity to nicotine (i.e. during early tobacco exposure), perhaps helping to explain differential vulnerability to nicotine dependence. This study explored associations of functional candidate gene polymorphisms with initial sensitivity to nicotine in 101 young adult nonsmokers of European ancestry. Nicotine (0, 5, 10 microg/kg) was administered through nasal spray followed by mood, nicotine reward (e.g. 'liking') and perception (e.g. 'feel effects') measures, physiological responses, sensory processing (prepulse inhibition of startle), and performance tasks. Nicotine reinforcement was assessed in a separate session using a nicotine versus placebo spray choice procedure. For the dopamine D4 receptor [DRD4 variable number of tandem repeats (VNTR)], presence of the 7-repeat allele was associated with greater aversive responses to nicotine (decreases in 'vigor', positive affect, and rapid information processing; increased cortisol) and reduced nicotine choice. Individuals with at least one DRD4 7-repeat allele also reported increased 'feel effects' and greater startle response, but in men only. Other genetic associations were also observed in men but not women, such as greater 'feel effects' and anger, and reduced fatigue, in the dopamine D2 receptor (DRD2 C957T single nucleotide polymorphism) TT versus CT or CC genotypes. Very few or no significant associations were seen for the DRD2/ANKK1 TaqIA polymorphism, the serotonin transporter promoter VNTR or 5HTTLPR (SLC6A4), the dopamine transporter 3' VNTR (SLC6A3), and the mu opioid receptor A118G single nucleotide polymorphism (mu opioid receptor polymorphism 1). Although these results are preliminary, this study is the first to suggest that genetic polymorphisms related to function in the dopamine D4, and perhaps D2, receptor may modulate initial sensitivity to nicotine before the onset of dependence and may do so differentially between men and women.
基因变异可能会影响对尼古丁的初始敏感性（即在早期接触烟草期间），这或许有助于解释对尼古丁依赖的易感性差异。本研究在101名欧洲血统的年轻成年不吸烟者中，探讨了功能性候选基因多态性与对尼古丁初始敏感性之间的关联。通过鼻喷雾剂给予尼古丁（0、5、10微克/千克），随后进行情绪、尼古丁奖赏（如“喜好”）和感知（如“感觉效果”）测量、生理反应、感觉加工（惊吓前脉冲抑制）以及行为任务。在单独的实验环节中，使用尼古丁与安慰剂喷雾选择程序评估尼古丁强化作用。对于多巴胺D4受体[DRD4可变串联重复序列（VNTR）]，7重复等位基因的存在与对尼古丁更强的厌恶反应相关（“活力”、积极情绪和快速信息处理能力下降；皮质醇增加）以及尼古丁选择减少。至少携带一个DRD4 7重复等位基因的个体也报告了“感觉效果”增加和惊吓反应增强，但仅在男性中如此。在男性而非女性中还观察到了其他基因关联，例如在多巴胺D2受体（DRD2 C957T单核苷酸多态性）中，TT基因型与CT或CC基因型相比，“感觉效果”更强、愤怒情绪更强以及疲劳感减轻。对于DRD2/ANKK1 TaqIA多态性、血清素转运体启动子VNTR或5HTTLPR（SLC6A4）、多巴胺转运体3' VNTR（SLC6A3）以及μ阿片受体A118G单核苷酸多态性（μ阿片受体多态性1），几乎未观察到显著关联或无显著关联。尽管这些结果是初步的，但本研究首次表明，与多巴胺D4以及可能还有D2受体功能相关的基因多态性，可能在依赖开始之前调节对尼古丁的初始敏感性，并且在男性和女性之间可能存在差异调节。
