Nicotine Reinforcement and Aversion in Young Adult Light Smokers

摘要：尼古丁被认为是烟草中的主要成瘾成分。因此，尼古丁 烟草产品的含量可作为制定有效控烟措施的合理目标 政策。在他们具有里程碑意义的文章中，Benowitz和Henningfield(B&H)建议逐步降低 香烟中的尼古丁含量低于使人上瘾的阈值剂量可能会阻止这种疾病的发生 在年轻吸烟者中尼古丁成瘾的风险。B&H估计尼古丁成瘾的门槛是 每支香烟大约释放0.17毫克尼古丁，并预测低于这一剂量的尼古丁剂量 Threshold既不会自行给药，也不会保持尼古丁成瘾。虽然提出了20多年的建议 以前，这一估计的尼古丁强化阈值仍然需要仔细系统地评估 受控的人体研究。这些知识的可获得性将为 尼古丁减少方法的潜在风险和好处。这种知识差距在一定程度上是由于难度 在评估尼古丁对人类目前可用的尼古丁递送系统的增强作用时。而当 一些尼古丁递送系统不能可靠地增强效果(例如，尼古丁口香糖或含片)，其他的则不能 准确的尼古丁剂量或提供除尼古丁之外的许多其他化学品(例如，烟草或e- 香烟)。为了解决这些局限性，我们开发了一种新型静脉(IV)尼古丁自身 人类的管理(NSA)模型。静脉注射尼古丁能很好地模拟药代动力学和行为学 烟熏尼古丁的影响，包括强化作用。该项目的主要目标是使用IV NSA进行 估算尼古丁的阈值强化剂量并生成低剂量尼古丁的剂量-效应曲线 在吸烟者身上。该应用程序还将检查尼古丁强化阈值和剂量-效应曲线 因性别和尼古丁代谢率而异。研究样本将是年轻成年男性和 女性轻度吸烟者和间歇性吸烟者，也被称为“吸烟者”，她们很少或根本没有上瘾的迹象。 我们提出了一项双盲、安慰剂对照的交叉研究，将招募36名男性和36名女性LITS。 吸烟者将参加五个实验阶段。在每堂课中，他们将首先抽样指定的 尼古丁剂量和安慰剂(生理盐水)剂量，然后有机会在尼古丁和 安慰剂给药。从这项研究中获得的知识将有助于指导降低 烟草产品中的尼古丁含量，以降低其成瘾潜力。

Abstract: Nicotine is considered to be the main addictive ingredient in tobacco. Therefore, the nicotine content of tobacco products may serve as a logical target in the development of effective tobacco-control policies. In their landmark article, Benowitz and Henningfield (B&H) proposed that the gradual reduction of the nicotine content of cigarettes to an amount below the threshold addictive dose could prevent the development of nicotine addiction among young smokers. B&H estimated that the threshold for nicotine addiction is approximately 0.17 mg of delivered nicotine per cigarette and predicted that nicotine doses below this threshold would neither be self-administered nor maintain nicotine addiction. Although proposed over 20 years ago, this estimated threshold for nicotine reinforcement remains to be systematically evaluated by carefully controlled human studies. Availability of such knowledge would provide a stronger scientific rationale for the potential risks and benefits of nicotine reduction approaches. This knowledge gap is partly due to the difficulty in assessing nicotine's reinforcing effects from currently available nicotine delivery systems in humans. While some nicotine delivery systems are not reliably reinforcing (e.g., nicotine gum or lozenge), others do not deliver accurate doses of nicotine or deliver many other chemicals in addition to nicotine (e.g., tobacco or e- cigarettes). To address these limitations, we have developed a novel intravenous (IV) nicotine self- administration (NSA) model for humans. IV nicotine closely mimics both the pharmacokinetics and behavioral effects of smoked nicotine, including reinforcement. The main goal of this project is to use IV NSA for estimating threshold reinforcing doses of nicotine and to generate dose-effect curves for low doses of nicotine in smokers. This application will also examine if the nicotine reinforcement threshold and dose-effect curve varies with gender and with the rate of nicotine metabolism. The study sample will be young adult male and female light and intermittent smokers (LITS), also known as `chippers', who show few or no signs of addiction. We propose a double-blind, placebo-controlled, crossover study that will enroll 36 male and 36 female LITS. Smokers will participate in five experimental sessions. In each session, they will first sample the assigned nicotine dose and the placebo (saline) dose followed by the opportunity to choose between nicotine and placebo administrations. The knowledge gained from this study will be useful in guiding strategies that lower nicotine content of tobacco products in order to reduce their addictive potential.