Impact of Adding Tobacco Constituents Nornicotine and Anatabine on Self-Administered Nicotine.

项目摘要/摘要 最近电子尼古丁传递系统(END)或电子烟的使用增加了人们对 尼古丁与烟草成分化合物在烟草滥用责任中的相对贡献 产品。这些尼古丁雾化器原本是设计用来戒烟的，现在正在 作为烟草的安全替代品，市场上有一系列令人眼花缭乱的可用口味和尼古丁含量。 由于普遍存在一种误解，即使用烟蒂不会有害，因为烟草不会燃烧，因此有一种 逐渐崛起的人群，他们开始对尼古丁上瘾的方式是将这些末端蒸发掉，而不是 通过实际的烟草产品。因此，这一人群预先接触了尼古丁，并可能处于 随之而来的是更大的烟草依赖风险。事实上，有早期证据表明，那些 开始以末端形式消费尼古丁的人向烟草消费过渡的机会比 他们从不使用的同龄人。尼古丁和烟草成分化合物之间的相互作用还没有 在尼古丁预暴露后烟草滥用风险增加的背景下解决了这一问题。这个 这项研究的目的是通过评估添加 在男性和男性静脉给药模型中尼古丁的成分 雌性、成年和青春期大鼠。在目标1中，去甲尼古丁和阿那他滨将被添加到自我给药中 成人尼古丁；在目标2中，去甲尼古丁和阿那他滨将被添加到自我给药的尼古丁中 青少年。在这两个目标中，我们将评估添加的成分化合物对激励的影响 尼古丁的价值。在每个目标中添加一种成分化合物的效果预计会减少简单的自我 给药是因为它们对烟碱型乙酰胆碱受体的兴奋作用提供了一定水平的尼古丁 换人。然而，去甲尼古丁，而不是那他滨，也被证明具有增强作用， 这可能是因为它对α4β2*受体有更大的亲和力。因此，去甲尼古丁，而不是那他滨，是 预计将提高尼古丁的激励价值，通过按累进比率重复治疗来衡量 明细表，因为该附加钢筋值。成分添加的不同影响 尼古丁对化合物的依赖将为烟草依赖的坚韧提供一个独特的视角。的确， 目前关于烟草成分化合物对尼古丁滥用倾向的影响的研究进展 围绕监管的研究主要集中在降低烟草中尼古丁含量的影响上。目前的研究， 然而，将调查尼古丁与烟草成分化合物对 从开始吸食尼古丁的新兴人群的角度看烟草制品的滥用责任 与烟头一起使用，而不是烟草。这一概念上的创新方法结合了药理学 使用重复的累进比率时间表操纵动机评估将使我们能够开始 来解决一个只可能随着时间的推移而增长的问题。

PROJECT SUMMARY/ABSTRACT The recent rise in the use of electronic nicotine delivery systems (ENDS), or e-cigarettes, is fueling interest in the relative contribution of nicotine versus constituent tobacco compounds in the abuse liability of tobacco products. Originally designed to be used as smoking cessation aids, these nicotine vaporizers are being marketed as safe alternatives to tobacco with a dizzying array of available flavors and levels of nicotine content. Because of the wide misconception that use of ENDS is not harmful because tobacco is not burned, there is a gradually-emerging population who are initiating their nicotine addiction by ‘vaping’ these ENDS rather than through actual tobacco products. This population is therefore pre-exposed to nicotine, and may be at subsequent greater risk for tobacco dependence. Indeed, there is early evidence that those individuals who begin consuming nicotine in ENDS form have a greater chance of transitioning to tobacco consumption than their never-using peers. The interactions between nicotine and constituent tobacco compounds have not yet been addressed in the context of this enhanced risk of tobacco abuse following nicotine pre-exposure. The objective of this research is to fill that scientific gap by assessing the impact of the addition of constituent compounds to nicotine in an intravenous self-administration model in male and female adult and adolescent rats. In Aim 1, nornicotine and anatabine will be added to self-administered nicotine in adults; in Aim 2, nornicotine and anatabine will be added to self-administered nicotine in adolescents. In both Aims, we will assess the impact of the added constituent compound on the motivational value of nicotine. The effect of adding a constituent compound in each Aim is expected to reduce simple self- administration because their agonist actions at nicotinic acetylcholine receptors provides a level of nicotine substitution. However, nornicotine, but not anatabine, has also been shown to have reinforcing properties, likely due to its far greater relative affinity for α4β2* receptors. Therefore, nornicotine, but not anatabine, is expected to enhance the motivational value of nicotine as measured by repeated sessions on a progressive ratio schedule because of this additive reinforcement value. A differential impact of the addition of constituent compounds to nicotine will provide a unique perspective on the tenacity of tobacco dependence. Indeed, current investigations of the impact of tobacco constituent compounds on nicotine abuse liability revolve around regulatory research focused on the effects of reducing nicotine content in tobacco. The current study, however, will investigate the relative contribution of nicotine versus constituent tobacco compounds on the abuse liability of tobacco products from the perspective of this emerging population who begin their nicotine use with ENDS rather than tobacco. This conceptually innovative approach incorporating pharmacological manipulations with motivational assessments using repeated progressive ratio schedules will allow us to begin to address a problem that is only likely to grow with time.