Threshold Dose for Nicotine Discrimination in Cigarettes

说明(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区分尼古丁的内感刺激作用与吸烟的阈值剂量。尽管关于尼古丁歧视的动物研究已经进行了半个世纪，之前的人类研究也对区分尼古丁以外的药物的阈值剂量进行了研究，但由于难以控制烟草摄入量的尼古丁剂量，还没有研究清楚地评估通过香烟在人类中识别尼古丁的阈值。到目前为止，由于我们的实验室拥有评估人类尼古丁歧视的最丰富经验(包括烟草以外的尼古丁配方)，我们建议使用经过充分验证的行为歧视方法来识别使用NIDA药物供应计划的尼古丁研究香烟(NRC)进行歧视的香烟尼古丁阈值剂量。我们将评估100名健康男性和女性吸烟者的不同样本的阈值剂量，这些样本的依赖程度和薄荷醇偏好不同，以产生证据，为制定烟草香烟中最高尼古丁含量的政策提供信息，以防止依赖的发生和维持。我们假设，这种区分尼古丁的阈值剂量将低于大多数当前商业品牌的产量，后者通常超过0.4毫克。我们还假设，非依赖型吸烟者的阈值剂量将低于依赖型吸烟者，男性与女性的阈值剂量将较低，可能是香烟薄荷醇偏好的函数，这与之前关于尼古丁敏感性差异的研究一致。重要的是，这项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识别阈值剂量和强化阈值剂量之间的关系。这项研究具有非常重要的意义，因为将尼古丁香烟的剂量限制在这一阈值剂量以下，可以将非依赖吸烟者升级为依赖的风险降至最低，并使依赖吸烟者更容易戒烟。因此，R21符合FDA烟草产品中心(CTP)的主要研究目标，特别是那些涉及通过改变尼古丁水平来减少烟草产品成瘾的研究目标，包括潜在的脆弱人群，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.