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

尼古丁替代疗法（NRT）是戒烟的常用药物治疗。某些NRT制剂的临床有效性程度似乎存在个体差异。由于经皮（TN）和鼻喷雾尼古丁（NS）之间的尼古丁递送速度差异很大，因此疗效的某些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。多巴胺转运蛋白基因型的差异，SLAGA 3 -9（“受保护”）与SLC 6A 3- *（“易患”），与吸烟状态有关，可能是因为尼古丁对多巴胺能奖励系统的不同影响。作为主要中心申请的一部分，计划进行一项戒烟研究（项目#2），以检查多巴胺转运蛋白基因型是否可以预测TN与NS治疗的不同结局。 该项目包括在开始NRT之前评估吸烟的强化价值。目前的试点研究扩展和补充的临床研究，检查在受控条件下，是否加强吸烟的价值，以响应急性暴露于TN与可能差异降低吸烟者之间的一种基因型或其他。在该试验项目中，我们提出：1）在具有SLC 6A 3 - 9与SLC 6A 3-* 多巴胺基因型的吸烟者之间，比较用TN、NS和安慰剂急性预处理后吸烟的强化值。我们预测，吸烟的强化值将减少更多的NS与TN（NRT型的主要影响），这种减少将不同的基因型（基因型× NRT型的相互作用）的函数。在SLC 6A 3-* 吸烟者中，NS会降低吸烟的增强值，但TN不会，而在SLC 6A 3 -9吸烟者中，NS或TN都会降低吸烟的增强值。2)比较多巴胺基因型对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，与SLC 6A 3 -9基因型相比，SLC 6A 3-* 基因型吸烟者的积极主观反应（例如，“警觉”，“放松”）将更多地通过NS增加，而对TN的情绪反应（基因型x NRT相互作用）的组间预期存在差异。该试验的结果可能有助于解释TN和NS在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从其他NRT制剂（即定制药物治疗）中获益的吸烟者。

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).