Threshold Dose for Nicotine Discrimination in Cigarettes

描述（申请人提供）：香烟中产生烟草强化和依赖性的最低（即阈值）尼古丁剂量几乎肯定不低于区分尼古丁内感受性刺激效应与吸烟的阈值剂量。尽管关于尼古丁辨别的动物研究和先前关于辨别除尼古丁以外的药物的阈值剂量的人类研究已经进行了半个世纪，但是由于难以控制烟草摄入的尼古丁剂量，因此没有研究明确评估人类通过香烟的尼古丁辨别阈值。由于我们的实验室迄今为止在评估人类尼古丁辨别方面经验最丰富（包括阈值剂量，使用除烟草外的尼古丁制剂），因此我们建议采用经过充分验证的行为辨别方法，使用NIDA药物供应计划的尼古丁研究香烟（NRC）确定香烟尼古丁阈值剂量。我们将在100名健康男性和女性吸烟者的不同样本中评估阈值剂量，这些吸烟者的依赖程度和薄荷醇偏好各不相同，以产生证据，为制定烟草卷烟中最大尼古丁含量的政策提供信息，从而防止依赖的发生和维持。我们假设，这个尼古丁阈值剂量的歧视将低于目前大多数商业品牌的产量，通常超过0.4毫克。我们还假设非依赖性吸烟者与依赖性吸烟者、男性与女性的阈值剂量较低，这可能是卷烟薄荷醇偏好的函数，与先前关于尼古丁敏感性差异的研究一致。重要的是，本研究还将单独评估这些香烟中尼古丁的自我给药，以确定吸烟中尼古丁辨别阈值剂量和强化阈值剂量之间的关系。这项研究是非常重要的，因为限制尼古丁香烟的量低于这个阈值剂量可以最大限度地减少非依赖性吸烟者升级为依赖性的风险，并使依赖性吸烟者更容易戒烟。因此，该R21解决了FDA烟草制品中心（CTP）的关键研究目标，特别是那些涉及通过改变尼古丁水平来减少烟草制品成瘾的目标，包括潜在的弱势群体，以及烟草使用的不良健康后果。

DESCRIPTION (provided by applicant): The lowest (i.e. threshold) nicotine dose in cigarettes that produces tobacco reinforcement and dependence is almost certainly not lower than the threshold dose for discrimination of nicotine's interoceptive stimulus effects from smoking. Despite a half century of animal research on nicotine discrimination and prior human studies of threshold dose for discriminating drugs other than nicotine, no research has clearly assessed this nicotine discrimination threshold in humans via cigarettes because of difficulty controlling nicotine dosing with tobacco intake. Because our lab has, by far, the most experience assessing nicotine discrimination in humans (including threshold dose, with a nicotine formulation other than tobacco), we propose to employ well- validated behavioral discrimination methodology to identify the cigarette nicotine threshold dose for discrimination using nicotine research cigarette (NRC) from the NIDA Drug Supply Program. We will assess threshold doses in a diverse sample of 100 healthy male and female smokers varying in dependence level and menthol preference to generate evidence that informs policy on establishing a maximum nicotine content in tobacco cigarettes that could prevent the onset and maintenance of dependence. We hypothesize that this nicotine threshold dose for discrimination will be lower than the yield of most current commercial brands, which typically exceed 0.4 mg. We also hypothesize that the threshold dose will be lower in nondependent vs. dependent smokers, in men vs. women, and perhaps as a function of cigarette menthol preference, consistent with prior research on differences in nicotine sensitivity. Importantly, this study will also separately assess self-administration of nicotine from these cigarettes to determine the relationship between nicotine discrimination threshold dose and reinforcement threshold dose in smoking. This research is highly significant because limiting nicotine cigarettes to amounts below this threshold dose could minimize risk of nondependent smokers escalating to dependence and make it easier for dependent smokers to quit smoking. As such, this R21 addresses key research objectives of the FDA's Center for Tobacco Products (CTP), notably those involving reducing addiction to tobacco products by modifying nicotine levels, including in potentially vulnerable populations, and adverse health consequences of tobacco use.