Dopaminergic variants involved in smoking behavior: A perfusion fMRI study

描述（由申请人提供）：吸烟成瘾是一个主要的公共卫生和经济问题，是可预防死亡的首要原因。从理论上讲，有两个主要因素导致持续吸烟和复发：吸烟线索引起的渴望（SCs）和尼古丁戒断引起的渴望（WD）。我们已经证明SC与非SC激活中皮质边缘奖励回路，并且渴望与大脑活动相关。尽管整体线索效应很强，但在大脑反应和渴望方面存在相当大的个体差异。由于多巴胺（DA）是药物奖励的关键神经递质，并通过其信号释放，我们假设遗传驱动的DA传递变异可能解释了观察到的大脑和行为反应的个体差异。在初步研究中，我们观察到携带“效率较低”的DA转运体（DAT）基因9可变核苷酸串联重复序列（VNTR）的吸烟者在暴露于SCs时，与10个VNTR纯合子相比，在我们的先验区域显示出增强的大脑激活。这支持了DAT 9等位基因与DAT基因的低表达相关的证据，这可能反映了较慢的DA清除，延长了奖励信息。我们假设，这种和其他da能成分的遗传变异可能赋予SCs和/或WD症状的易感性，从而增加复发的可能性。为了开始验证这一假设，我们将利用灌注功能磁共振成像，吸烟行为分析和功能候选基因关联方法来检查吸烟者在饱腹和WD暴露于SCs时的大脑和行为活动。具体来说，目标1)我们将检查48名吸烟者的大脑活动，他们将接受两次平衡扫描，一次是在饱腹时，另一次是（在一段时间的监控下）戒烟。目的2)在两种情况下，我们将研究自然吸烟行为对SCs的反应。吸烟者会在每次吸烟前后对自己的渴望程度和WD进行评分。在每次扫描之后，吸烟者将有机会吸烟，在此期间将收集有关吸烟潜伏期和香烟消费的数据，有效地将大脑和行为反应联系起来。目的3)我们将研究遗传因素对区域CBF变化和行为反应的影响，这些变化是WD和sc诱导的香烟渴望的基础。DNA样本将被分析多巴胺能基因的等位基因变异，如负责DA再摄取的DAT；参与DA分解代谢的儿茶酚o-甲基转移酶（COMT）基因；DA受体（D2和D4）亚型。该建议的一个强大特征是将大脑，渴望和遗传与实际吸烟行为联系起来，为未来的工作提供基础，在此期间可以检查基因变异的治疗结果，最终建立大脑/行为/遗传内表型，这样戒烟治疗可以结构化以满足个人需求并减少复发的可能性。公共卫生相关性：拟议的项目将利用灌注功能磁共振成像，吸烟行为分析和多巴胺能成瘾靶向多态性的功能候选基因关联方法来检查吸烟者在暴露于吸烟提醒时的饱腹和戒断条件下的大脑和行为活动。这些研究将为未来的研究提供基础，在这些研究中，治疗策略和治疗结果可以根据吸烟者的遗传亚群进行检查。最终，如果大脑/行为/基因内表型可以在治疗前确定，戒烟治疗就可以根据个人需要进行结构化设计。

DESCRIPTION (provided by applicant): Cigarette addiction is a major public health and economic problem and is the premier cause of preventable death. It is theorized that two major factors contribute to continued smoking and relapse: craving elicited by smoking cues (SCs) and craving elicited by nicotine withdrawal (WD). We have demonstrated that SC vs. nonSCs activate the mesocorticolimbic reward circuitry and that craving correlated with brain activity. Despite a robust overall cue effect, there was considerable individual variability in the brain response and in craving. As dopamine (DA) is a critical neurotransmitter for drug reward and is released by its signals, we hypothesize that genetically driven variation in DA transmission may account for the observed individual differences in brain and behavioral responses. In preliminary work we observed that smokers who are carriers of the `less efficient' DA transporter (DAT) gene 9 variable nucleotide tandem repeat (VNTR) show enhanced brain activation in our a priori regions during exposure to SCs compared to 10 VNTR homozygotes. This supports evidence that the DAT 9 allele is associated with lower expression of the DAT gene, which may reflect slower DA clearance, prolonging the reward message. We posit that genetic variability in this and other DA-ergic components may confer a susceptibility to SCs and/or WD symptoms that increase the probability of relapse. To begin to test this hypothesis we will utilize perfusion fMRI, smoking behavioral assays and a functional candidate gene association approach to examine the brain and behavioral activity of smokers under conditions of satiety and WD during exposure to SCs. Specifically, Aim 1) we will examine brain activity in 48 smokers who will undergo two counterbalanced scanning sessions, one while satiated and one [following a period of monitored] abstinence. Aim 2) we will examine naturalistic smoking behavior in response to SCs under both conditions. Smokers will rate their craving and WD before and after each session. Following each scan smokers will be given the opportunity to smoke during which data on latency to smoke and cigarette consumption will be collected, effectively linking brain and behavioral responses. Aim 3) we will examine the genetic contribution to the regional CBF changes and behavioral responses underlying WD- and SC-induced cigarette craving. DNA samples will be analyzed for allelic variance in dopaminergic genes, such as the DAT, responsible for DA reuptake; the catechol-o-methyltransferase (COMT) gene, involved in DA catabolism; and the DA receptor (D2 and D4) subtypes. One powerful feature of this proposal is to link brain, craving and genetics to actual smoking behavior, providing the foundation for future work during which treatment outcome can be examined with respect to gene variance, ultimately establishing a brain/behavioral/genetic endophenotype, such that smoking cessation treatments can be structured to meet individual needs and reduce the probability of relapse. PUBLIC HEALTH RELEVANCE: The proposed project will utilize perfusion fMRI, smoking behavioral assays and a functional candidate gene association approach of dopaminergic addictions-targeted polymorphisms to examine the brain and behavioral activity of smokers under conditions of satiety and withdrawal during exposure to smoking reminders. These studies will provide the foundation for future studies during which treatment strategies and treatment outcome and can be examined with respect to genetic subgroups of smokers. Ultimately, if a brain/behavioral/genetic endophenotype can be determined in advance of treatment, smoking cessation treatments can be structured to meet individual needs.