Polymorphisms Related to Dopamine Receptor Function and Smoking

描述(由申请者提供)：几种成瘾理论认为，依赖吸烟是由于奖赏过程的不平衡造成的，以至于香烟和吸烟相关的刺激变得“被高估”，和/或其他不吸烟的增强剂被“低估”。然而，在长期吸烟者中，已经观察到对吸烟和不吸烟刺激的神经和行为反应存在很大的个体差异。因此，个体在奖赏处理上的差异--要么存在于基线水平，要么是由于长期接触尼古丁--可能是导致易受尼古丁依赖和复发的一个重要因素。多巴胺是一种参与奖赏处理的关键神经递质，越来越多的证据表明，与多巴胺受体功能相关的基因多态性影响尼古丁和非药物增强剂的处理。此应用程序的目的是利用已建立的人体实验室程序和功能神经成像来严格评估DRD2/ANKK1 Taq IA和DRD4 VNTR基因多态对吸烟和不吸烟奖励处理的影响，并最终评估在受到激励时实现戒烟的能力。具体目的是：1)确定DRD2/ANKK Taq IA和DRD4 VNTR基因多态性是否预测吸烟者对吸烟和不吸烟奖励的神经反应；2)确定这些相同的基因多态性是否预测吸烟者对吸烟和不吸烟奖励的行为反应；3)确定当给予戒烟金钱激励时，这些基因多态性是否预测戒烟的能力。4)确定在基于激励的测试中，这些基因多态与戒烟能力之间的关系是否通过吸烟者对吸烟的反应和非吸烟奖励来调节。在拟议的研究中，我们将招募受试者(N=80)，以2x2受试者之间的设计为基础。一半的参与者将由TaqIA变体A1等位基因的携带者组成，另一半将由DRD4 VNTR的7R(7重复)等位基因的携带者组成。我们预测，携带TaqIA基因A1等位基因的戒烟者将在与奖励相关的区域表现出对非吸烟奖励的血液氧合水平依赖性(BOLD)反应降低，以及对非吸烟奖励的行为反应降低，而DRD4 VNTR的7R等位基因携带者将对吸烟奖励表现出增强的大胆反应，并对吸烟奖励的行为影响表现出超敏反应。我们进一步预测，携带Taq IA多态的A1等位基因或DRD4 VNTR的7R等位基因的个体将在戒烟的实验模型中较难戒烟，在该模型中，戒烟通过金钱来加强。最后，我们预测这一效应将通过与奖励敏感性相关的更接近的内表型来调节。这些发现将有助于阐明与D2和D4受体相关的多态可能导致吸烟和复发风险的重要途径。 与公共健康相关：尼古丁的使用和依赖与奖励过程的不平衡有关，在这种情况下，吸烟被“高估”，而不吸烟的替代品被“低估”。这些变化并不是在所有吸烟者身上都一样明显。一个可能的变异来源是遗传；与多巴胺受体功能相关的多态既与暗示诱导的渴望有关，也与对非吸烟奖励的敏感性有关。这里提出的实验将探索与D2和D4多巴胺受体相关的遗传变异、对吸烟和不吸烟奖励的神经生物学和行为反应，以及在给予金钱激励时戒烟的能力之间的关系。

DESCRIPTION (provided by applicant): Several theories of addiction posit that dependent smoking results from an imbalance in reward processing, such that cigarettes and smoking related stimuli become "overvalued" and/or other non-smoking reinforcers are "undervalued". Yet among chronic smokers, substantial individual variability has been observed in the neural and behavioral responses to both smoking and non-smoking stimuli. Thus, individual differences in reward processing-either present at baseline or resulting from chronic nicotine exposure-might be an important factor contributing to vulnerability to nicotine dependence and relapse. Dopamine is a key neurotransmitter involved in reward processing, and there is growing evidence that polymorphisms related to dopamine receptor function impact processing of both nicotine and non-drug reinforcers. The purpose of this application is to utilize established human laboratory procedures and functional neuroimaging to rigorously assess the impact of DRD2/ANKK1 Taq IA and DRD4 VNTR polymorphisms on the processing of both smoking and non-smoking rewards, and ultimately, the ability to achieve abstinence when given an incentive to do so. The specific aims are: 1) To determine whether the DRD2/ANKK Taq IA and DRD4 VNTR polymorphisms predict neural response to smoking and non-smoking reward in smokers; 2) To determine whether these same polymorphisms predict behavioral response to smoking and non-smoking reward in smokers; 3) To determine whether these polymorphisms predict the ability to refrain from smoking when given a monetary incentive for abstinence. 4) To determine whether the relationship between these polymorphisms and the ability to achieve abstinence in an incentive-based test is mediated by responsiveness to smoking and non-smoking reward in smokers. In the proposed study, we will recruit participants (N=80) based on genotype in a 2 x 2 between subjects design. Half the participants will be comprised of individuals who are carriers for the A1 allele of the TaqIA variant and half will be comprised of individuals who are carriers for the 7R (7 repeat) allele of the DRD4 VNTR. We predict that abstinent smokers who are carriers of the A1 allele of the TaqIA polymorphism will demonstrate reduced Blood Oxygenation Level-Dependent (BOLD) response to non- smoking rewards in reward-related areas as well as reduced behavioral responsiveness to non-smoking reward, while carriers of the 7R allele of the DRD4 VNTR will demonstrate potentiated BOLD response to smoking rewards and hypersensitivity to the behavioral effects of smoking rewards. We further predict that individuals carrying the A1 allele of the Taq IA polymorphism or a 7R allele of the DRD4 VNTR will be less able to refrain from smoking during an experimental model of relapse in which abstinence is reinforced with money. Finally, we predict that this effect will be mediated by the more proximal endophenotypes related reward sensitivity. These findings would help to elucidate important pathways by which polymorphisms related to the D2 and D4 receptors might confer risk for smoking and relapse. PUBLIC HEALTH RELEVANCE: Nicotine use and dependence is associated with an imbalance in reward processing in which smoking is "overvalued" and non-smoking alternatives are "undervalued." These changes do not manifest equally in all smokers. One possible source of variance is genetics; polymorphisms related to dopamine receptor function are related to both cue-induced craving and to sensitivity to non-smoking rewards. The experiment proposed here will explore the relationship between genetic variants related to the D2 and D4 dopamine receptors, the neurobiological and behavioral responsiveness to both smoking and non-smoking rewards, and the ability to refrain from smoking when given a monetary incentive to do so.