Polymorphisms Related to Dopamine Receptor Function and Smoking

描述（由申请人提供）：成瘾的几种理论认为，依赖性吸烟是奖励处理不平衡的结果，使得香烟和吸烟相关刺激变得“被高估”和/或其他非吸烟刺激被“低估”。然而，在慢性吸烟者中，在对吸烟和非吸烟刺激的神经和行为反应中观察到了很大的个体差异。因此，奖励过程中的个体差异-无论是在基线或慢性尼古丁成瘾-可能是一个重要的因素，有助于尼古丁依赖和复发的脆弱性。多巴胺是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多态性影响尼古丁和非药物刺激剂的处理。本申请的目的是利用已建立的人类实验室程序和功能性神经成像来严格评估DRD 2/ANKK 1 Taq IA和DRD 4 VNTR多态性对吸烟和不吸烟奖励的处理的影响，并最终评估当给予激励时实现戒烟的能力。具体目标是：1）确定DRD 2/ANKK Taq IA和DRD 4 VNTR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）确定这些多态性是否预测当给予戒烟的金钱激励时避免吸烟的能力。4)确定这些多态性与在基于激励的测试中实现戒烟的能力之间的关系是否通过吸烟者对吸烟和不吸烟奖励的反应来介导。在拟定的研究中，我们将根据基因型招募受试者（N=80），采用2 x 2受试者间设计。一半参与者将由TaqIA变体A1等位基因携带者组成，另一半将由DRD 4 VNTR 7 R（7次重复）等位基因携带者组成。我们预测，携带TaqIA多态性A1等位基因的戒烟吸烟者将在奖励相关区域表现出对非吸烟奖励的血氧水平依赖性（BOLD）反应降低，以及对非吸烟奖励的行为反应降低，而DRD 4 VNTR的7 R等位基因的携带者将表现出对吸烟奖励的增强的BOLD反应和对吸烟的行为效应的超敏反应。吸烟奖励我们进一步预测，携带Taq IA多态性的A1等位基因或DRD 4 VNTR的7 R等位基因的个体在复发的实验模型中戒烟的能力较低，在该模型中，戒烟是用金钱来加强的。最后，我们预测，这种影响将介导的更近端的内表型相关的奖励敏感性。这些发现将有助于阐明与D2和D4受体相关的多态性可能赋予吸烟和复发风险的重要途径。 公共卫生相关性：尼古丁的使用和依赖与奖励过程的不平衡有关，在这种不平衡中，吸烟被“高估”，而非吸烟的替代品被“低估”。“这些变化在所有吸烟者中并不平等。变异的一个可能来源是遗传学;与多巴胺受体功能相关的多态性与线索诱导的渴望和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之间的关系，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避免吸烟的能力。

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.