GABA B agonists revisited: Brain, behavioral and genetic effects in smokers

描述（由申请人提供）：烟瘾是我国可预防死亡的主要原因。尽管吸烟对健康造成威胁生命的后果，并给社会造成沉重的经济负担，但仍有近25%的人口继续吸烟。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）。无法抵抗由厌食症引起的渴望，这种渴望在一个月内就会下降，这是早期复发的主要原因。然而，吸烟者报告说，SCs可能在戒烟数月甚至数年后引发复发。现有的戒烟药物可减轻WD和/或减少尼古丁奖励，对吸烟者亚群有帮助。然而，其他“易受线索影响”的吸烟者获得的益处较少，这表明迫切需要确定针对SC反应性的药物。许多因素，包括遗传变异，可能是SCs和WD对复发易感性的相对贡献的基础。事实上，我们已经发现多巴胺转运体SLC6A3 （DAT）基因变异对SC反应性的深远影响。我们的发现与多巴胺（DA）在药物奖励和药物相关线索中的既定作用一致。GABA - B激动剂调节DA，作为药物线索阻断剂已显示出前景。有证据表明，GABA B激动剂巴氯芬可以调节药物寻找和服用行为，因此可能是研究GABA B激动剂对SC反应性影响的“原型探针”。本提案的目标是确定sc易感药物反应性内表型。为了实现这一目标，我们将：AIM 1，确认由功能性da调节候选基因变异介导的SC易感内表型；AIM 2，利用我们创新的大脑/行为/遗传范式，将SC暴露期间“巴氯芬诱导的”神经反应与行为相关联系起来，以确定药物反应性内表型；探讨da调节基因的等位基因变异与巴氯芬诱导的脑和行为反应之间的相互作用。我们的模型将采用灌注功能磁共振成像的定量技术，这有助于测量药物诱导的（纵向）神经修饰，无论是在大脑“休息”还是在认知和情绪任务期间。因此，我们将获得吸烟者在3周药物治疗前后的静息基线和SC暴露数据。吸烟行为将采用“新颖的自然方法”进行监测。DNA样本将被分析da调节基因的等位基因变异。最终，当代医学的目标是建立预测药物反应的大脑/行为/遗传内表型，以便针对个体脆弱性进行量身定制的治疗（即个性化医疗）。拟议的研究将提供遗传影响和GABA激动剂机制对主要复发预测因子：SC反应性的知识。这将对吸烟治疗战略产生持续和持久的影响，并将有助于实现国家烟草开发协会制定的一项主要目标，即“根除烟草滥用和成瘾”。

DESCRIPTION (provided by applicant): Cigarette addiction is the leading cause of preventable death in our nation. Despite the life-threatening health consequences of smoking and the substantial heavy economic burden on society, close to 25% of the population continues to smoke. Two major factors contribute to continued smoking and relapse: craving elicited by smoking cues (SCs) and craving elicited by nicotine withdrawal (WD). Inability to combat WD-induced craving, which declines within a month, plays a major role in EARLY relapse. However, smokers report that SCs can trigger relapse months or even years after quitting. Existing smoking cessation medications alleviate WD and/or reduce nicotine reward, and are helpful for subgroups of smokers. However, other 'cue-vulnerable' smokers receive less benefit evincing the critical need to identify agents that target SC reactivity. A number of factors, including genetic variance, may underlie the relative contribution of SCs and WD to susceptibility to relapse. Indeed, we have found a profound effect of variance in the dopamine transporter SLC6A3 (DAT) gene on SC reactivity. Our findings are consistent with the well-established role of dopamine (DA) in drug reward and drug-associated cues. GABA B agonists modulate DA and have shown promise as drug cue blocking agents. Evidence suggests that the GABA B agonist, baclofen modulates drug seeking and taking behavior and thus may be a 'prototypical probe' to examine the effects of GABA B agonists on SC reactivity. The goal of this proposal is to identify a SC-vulnerable pharmaco-responsive endophenotype. Towards this goal, we will: AIM 1, confirm a SC-vulnerable endophenotype mediated by variance in functional DA-modulating candidate genes AIM 2, utilize our innovative brain/behavioral/genetic paradigm to link 'baclofen-induced' neural responses during SC exposure with behavioral correlates to identify a pharmaco-responsive endophenotype~ and Exploratory AIM: explore the interaction between allelic variance in DA-modulating genes and baclofen- induced brain and behavioral responses. Our model will employ the quantitative technique of perfusion fMRI, which facilitates the measurement of medication-induced (longitudinal) neural modifications, both in the brain 'at rest' and during cognitive and emotional tasks. Thus, we will acquire resting baseline and SC exposure data in smokers prior to and following a 3-week medication regimen. Smoking behavior will be monitored using 'novel naturalistic methods'. DNA samples will be analyzed for allelic variance in DA-regulating genes. Ultimately, the goal for contemporary medicine is to establish brain/behavioral/genetic endophenotypes that predict medication response, such that treatments are tailored to manage individual vulnerabilities (i.e., Personalized Medicine). The proposed studies will provide knowledge about genetic influences and GABA agonist mechanisms on a major relapse predictor: SC reactivity. This will have a sustained and lasting impact on smoking treatment strategies and will aid in meeting a major goal set by NIDA, which is to "Eradicate Tobacco Abuse and Addiction". PUBLIC HEALTH RELEVANCE: The proposed project will utilize perfusion fMRI, a functional candidate gene association approach (of dopaminergic addictions-targeted polymorphisms), and the dopamine-modulating and GABA B agonist, baclofen to examine the brain and behavioral responses in smokers to appetitive smoking reminders (cues that motivate continued smoking and relapse). These studies will provide a means to identify an appetitive cue- sensitive pharmaco-responsive endophenotype. Once brain/behavioral/genetic endophenotypes can be determined prior to treatment, smoking cessation treatments can be structured to meet individual needs, which will significantly improve treatment outcome.