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

重新审视 GABA B 激动剂：吸烟者的大脑、行为和遗传影响

• 批准号: 8542805
• 负责人: TERESA R FRANKLIN
• 金额: $ 32.65万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542805
• 关键词: Affect; Agonist; Amygdaloid structure; Anterior; Baclofen; Behavior; Behavioral; Behavioral Genetics; Brain; Candidate Disease Gene; Catechol O-Methyltransferase; Cessation of life; Cigarette; Cognitive; Consumption; Cues; DNA; Data; Decision Making; Dopamine; Dopamine Agonists; Dorsal; Economic Burden; Emotional; Exhibits; Functional Magnetic Resonance Imaging; GABA Agonists; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Health; Homozygote; Image; Individual; Insula of Reil; Intervention; Knowledge; Lateral; Life; Link; Longitudinal Studies; Measurement; Medial; Mediating; Medicine; Methods; Methyltransferase Gene; Modeling; Modification; Monitor; National Institute of Drug Abuse; Nicotine; Nicotine Withdrawal; Perfusion; Pharmaceutical Preparations; Placebos; Play; Population; Predisposition; Publishing; Randomized; Regimen; Relapse; Relative (related person); Reporting; Research Design; Rest; Rewards; Role; Sample Size; Sampling; Smoke; Smoker; Smoking; Smoking Behavior; Societies; Structure; Subgroup; Synapses; Techniques; Testing; Time; Tobacco Dependence; Treatment outcome; Variant; Ventral Striatum; Withdrawal; Withholding Treatment; addiction; combat; craving; cue reactivity; design; dopamine transporter; drug reward; endophenotype; gamma-Aminobutyric Acid; gene interaction; improved; innovation; meetings; novel; relating to nervous system; response; smoking cessation; smoking relapse; tobacco abuse; transmission process; treatment strategy

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".

描述(申请人提供)：吸烟成瘾是我国可预防死亡的首要原因。尽管吸烟危害生命健康，给社会带来沉重的经济负担，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：由吸烟线索(SC)引起的渴望和由尼古丁戒断(WD)引起的渴望。无法对抗WD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可能会在戒烟几个月甚至几年后引发复发。现有的戒烟药物可以缓解WD和/或减少尼古丁奖励，对吸烟者的亚群有帮助。然而，其他“易受影响的”吸烟者获得的好处较少，这表明迫切需要确定针对SC反应性的制剂。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)基因的变异对SC的反应性有深远的影响。我们的发现与多巴胺(DA)在药物奖励和药物相关线索中的作用是一致的。GABA B激动剂调节DA，并显示出作为药物线索阻滞剂的前景。有证据表明，GABA B激动剂巴氯芬调节药物寻找和服用行为，因此可能是检测GABA B激动剂对SC反应性影响的典型探针。这项建议的目标是确定一种对SC敏感的药物反应内表型。为了实现这一目标，我们将：目标1，确认由功能DA调节候选基因变异所介导的SC脆弱的内表型AIM 2，利用我们的创新的脑/行为/遗传范式将SC暴露期间由巴氯芬诱导的神经反应与行为相关联系起来，以确定药物敏感的内表型~和探索性目的：探索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。我们的模型将使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)神经修改，无论是在大脑的“静态”还是在认知和情感任务中。因此，我们将获得吸烟者在3周服药方案之前和之后的静息基线和SC暴露数据。吸烟行为将使用“新的自然主义方法”进行监测。DNA样本将被分析DA调节基因的等位基因变异。归根结底，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，以便为管理个体脆弱性而量身定做的治疗方法(即个性化医学)。拟议的研究将提供关于遗传影响和GABA激动剂机制对复发的主要预测因素：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NIDA设定的一个主要目标，即“根除烟草滥用和成瘾”。