Pilot--Nicotine replacement therapy effect on smoking reinforcement by genotype

试点--尼古丁替代疗法对基因型吸烟强化的影响

• 批准号: 6257819
• 负责人: KENNETH Alan PERKINS
• 金额: $ 24.52万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6257819
• 关键词: clinical research; dopamine transporter; genotype; human subject; human therapy evaluation; nicotine replacement; placebos; reinforcer; smoking cessation; tobacco abuse

Nicotine replacement therapy (NRT) is the common pharmacological treatment for smoking cessation. There appear to be individual differences in the degree to which some formulations of NRT are clinically efficacious. Because of the vastly different speed of nicotine delivery between transdermal (TN) and nasal spray nicotine (NS), some of this individual differences in efficacy may relate to different effects of these products on neurochemical responses. Differences in dopamine transporter genotype, SLAGA3-9 ("protected") versus SLC6A3- *("predisposed"), are related to smoking status, perhaps because of differential effects of nicotine on the dopaminergic reward system. A smoking cessation study (project #2) is planned as part of the main center application to examine whether dopamine transporter genotype may predict differential outcome with TN versus NS treatment. This project includes assessment of the reinforcing value of smoking prior to starting NRT. The present pilot study extends and complements the clinical study by examining under controlled conditions whether the reinforcing value of smoking in response to acute exposure to TN versus may be differentially reduced between smokers of one genotype or the other. In this pilot project, we propose to: 1) Compare the reinforcing value of smoking following acute pre- treatment with TN, NS, and placebo between smokers with the SLC6A3- 9 versus SLC6A3-* dopamine genotypes. We predict that the reinforcing value of smoking will be decreased more by NS versus TN (main effect of NRT type) and that this decrease will differ as a function of genotype (genotype x NRT type interaction). The reinforcing value of smoking will be decreased by NS, but not TN, in SLC6A3-* smokers, while the reinforcing value of smoking will be decreased by either NS or TN in SLC6A3-9 smokers. 2) Compare acute objective mood response to TN, NS, and placebo between dopamine genotypes. Although of secondary, we predict that positive subjective responses (e.g. "alert", "relaxed") will be increased by NS more in smokers with SLC6A3-* versus SLC6A3-9 genotypes, while differences are expected between groups in mood responses to TN (genotype x NRT interaction). Result of this pilot may help explain possible different clinical efficacy of TN and NS between genotypes and aid in the identification of smokers more likely to benefit from one of the other formulation of NRT (i.e. tailor pharmacotherapy).

尼古丁替代疗法(NRT)是戒烟常用的药物疗法。在某些NRT制剂的临床有效程度上，似乎存在个体差异。由于透皮尼古丁(TN)和鼻腔喷雾尼古丁(NS)之间尼古丁的传递速度有很大的不同，这种疗效的个体差异可能与这些产品对神经化学反应的不同影响有关。多巴胺转运蛋白SLAGA3-9(“受保护”)和SLC6A3-*(“易患”)的差异与吸烟状态有关，可能是因为尼古丁对多巴胺能奖赏系统的不同影响。计划进行一项戒烟研究(项目2)，作为主要中心应用的一部分，以检查多巴胺转运体基因是否可以预测TN和NS治疗的不同结果。该项目包括在开始NRT之前对吸烟的强化价值进行评估。目前的先导性研究是对临床研究的扩展和补充，研究在受控条件下，吸烟对急性暴露于TN的反应的强化价值是否在一种或另一种基因型的吸烟者之间有差异地降低。在这个试点项目中，我们建议：1)比较SLC6A3-9和SLC6A3-*多巴胺基因的吸烟者在接受TN、NS和安慰剂急性预治疗后吸烟的增强价值。我们预测，与TN(NRT类型的主效应)相比，NS对吸烟的强化作用将更大程度地降低，并且这种减少将因基因(基因x NRT类型交互作用)而不同。在SLC6A3-*吸烟者中，生理盐水会降低吸烟的增强值，但TN不会降低吸烟的增强值，而在SLC6A3-9吸烟者中，无论是NS还是TN都会降低吸烟的增强值。2)比较不同多巴胺基因型对TN、NS和安慰剂的急性客观情绪反应。虽然是次要的，但我们预测在携带SLC6A3-*与SLC6A3-9基因的吸烟者中，NS会更多地增加积极的主观反应(如“警觉”、“放松”)，而对TN的情绪反应(基因x NRT交互作用)预计会在不同组之间存在差异。这项试验的结果可能有助于解释TN和NS在不同基因型之间可能存在的不同临床疗效，并有助于识别更有可能受益于其他NRT配方之一的吸烟者(即量身定做的药物治疗)。