Department of Psychiatry, Yale University, New Haven, CT, USA.
Yale Positron Emission Tomography (PET) Center, Yale University, New Haven, CT, USA.
Nicotine Tob Res. 2022 Oct 17;24(10):1597-1606. doi: 10.1093/ntr/ntac026.
Tobacco smoking is a major public health burden. The first-line pharmacological treatment for tobacco smoking is nicotine replacement therapy (eg, the nicotine patch (NIC)). Nicotine acts on nicotinic-acetylcholine receptors on dopamine terminals to release dopamine in the ventral and dorsal striatum encoding reward and habit formation, respectively.
To better understand treatment efficacy, a naturalistic experimental design combined with a kinetic model designed to characterize smoking-induced dopamine release in vivo was used. Thirty-five tobacco smokers (16 female) wore a NIC (21 mg, daily) for 1-week and a placebo patch (PBO) for 1-week in a randomized, counter-balanced order. Following 1-week under NIC and then overnight abstinence, smokers participated in a 90-minute [11C]raclopride positron emission tomography scan and smoked a cigarette while in the scanner. Identical procedures were followed for the PBO scan. A time-varying kinetic model was used at the voxel level to model transient dopamine release peaking instantaneously at the start of the stimulus and decaying exponentially. Magnitude and spatial extent of dopamine release were estimated. Smokers were subcategorized by nicotine dependence level and nicotine metabolism rate.
Dopamine release magnitude was enhanced by NIC in ventral striatum and diminished by NIC in dorsal striatum. More-dependent smokers activated more voxels than the less-dependent smokers under both conditions. Under PBO, fast metabolizers activated more voxels in ventral striatum and fewer voxels in dorsal striatum compared to slow metabolizers.
These findings demonstrate that the model captured a pattern of transient dopamine responses to cigarette smoking which may be different across smoker subgroup categorizations.
This is the first study to show that NIC alters highly localized patterns of cigarette smoking-induced dopamine release and that levels of nicotine dependence and nicotine clearance rate contribute to these alterations. This current work included a homogeneous subject sample with regards to demographic and smoking variables, as well as a highly sensitive model capable of detecting significant acute dopamine transients. The findings of this study add support to the recent identification of biomarkers for predicting the effect of nicotine replacement therapies on dopamine function which could help refine clinical practice for smoking cessation.
吸烟是一个主要的公共卫生负担。尼古丁替代疗法（例如尼古丁贴片（NIC））是治疗吸烟的一线药物。尼古丁作用于多巴胺末梢的烟碱型乙酰胆碱受体，分别释放腹侧纹状体和背侧纹状体中的多巴胺，编码奖励和习惯形成。
为了更好地了解治疗效果，采用了自然实验设计，并结合了一种旨在体内描述吸烟诱导的多巴胺释放的动力学模型。35 名吸烟者（16 名女性）随机、平衡地佩戴 NIC（21mg，每日）一周和 PBO（安慰剂）一周。在 NIC 治疗一周后，经过一夜的禁欲，吸烟者参加了 90 分钟的 [11C]raclopride 正电子发射断层扫描扫描，并在扫描仪中吸烟。对于 PBO 扫描，遵循相同的程序。使用时变动力学模型在体素水平上对多巴胺的瞬时释放进行建模，该模型在刺激开始时瞬间达到峰值，并呈指数衰减。估计多巴胺释放的幅度和空间范围。根据尼古丁依赖水平和尼古丁代谢率对吸烟者进行分类。
NIC 增加了腹侧纹状体中的多巴胺释放幅度，并减少了背侧纹状体中的多巴胺释放幅度。在两种情况下，依赖性更强的吸烟者比依赖性较低的吸烟者激活了更多的体素。在 PBO 下，与慢代谢者相比，快代谢者在腹侧纹状体中激活了更多的体素，而在背侧纹状体中激活了更少的体素。
这些发现表明，该模型捕获了吸烟引起的多巴胺反应的瞬态模式，这些模式可能因吸烟者的亚组分类而异。
这是第一项表明 NIC 改变吸烟引起的多巴胺释放的高度局部模式的研究，并且尼古丁依赖水平和尼古丁清除率的水平有助于这些改变。目前的这项工作包括在人口统计学和吸烟变量方面具有同质性的受试者样本，以及一种能够检测到显著急性多巴胺瞬变的高度敏感模型。这项研究的结果为最近确定预测尼古丁替代疗法对多巴胺功能影响的生物标志物提供了支持，这可能有助于为戒烟的临床实践提供参考。
