Threshold Dose for Nicotine Discrimination in Cigarettes

描述（由申请人提供）：香烟中产生烟草强化和依赖的最低（即阈值）尼古丁剂量几乎肯定不低于吸烟对尼古丁的内感受性刺激效应的区分阈值剂量。尽管半个世纪以来对尼古丁辨别的动物研究和之前对除尼古丁以外的其他药物的阈值剂量的人类研究，但由于难以控制尼古丁的剂量与烟草的摄入量，没有研究明确地通过香烟评估人类的尼古丁辨别阈值。因为到目前为止，我们的实验室在评估人类尼古丁歧视方面（包括阈值剂量，使用烟草以外的尼古丁配方）的经验最多，我们建议采用经过充分验证的行为歧视方法，使用NIDA药物供应计划的尼古丁研究卷烟（NRC）来确定香烟尼古丁歧视的阈值剂量。我们将评估100名不同依赖程度和薄荷醇偏好不同的健康男性和女性吸烟者的不同样本的阈值剂量，以产生证据，为制定可预防依赖发生和维持的烟草卷烟中最大尼古丁含量的政策提供信息。我们假设这一尼古丁鉴别阈值剂量将低于目前大多数商业品牌的产量，后者通常超过0.4毫克。我们还假设，非依赖吸烟者与依赖吸烟者、男性与女性的阈值剂量会更低，这可能与香烟对薄荷醇的偏好有关，这与之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。这项研究非常重要，因为将尼古丁香烟的数量限制在这个阈值剂量以下，可以将非依赖吸烟者升级为依赖的风险降到最低，并使依赖吸烟者更容易戒烟。因此，本R21解决了FDA烟草制品中心（CTP）的主要研究目标，特别是通过改变尼古丁水平来减少烟草制品成瘾，包括潜在弱势群体，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.