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

项目总结/摘要 最近电子尼古丁输送系统（ENDS）或电子烟的使用增加， 尼古丁与烟草成分化合物在烟草滥用倾向中的相对贡献 产品.这些尼古丁蒸发器最初设计用于戒烟辅助， 作为烟草的安全替代品销售，具有令人眼花缭乱的各种口味和尼古丁含量。 由于广泛的误解，使用ENDS是无害的，因为烟草不燃烧，有一个 逐渐出现的人群通过“vaping”这些结束而不是“vaping”这些结束来开始尼古丁成瘾， 通过真正的烟草产品。因此，这一人群预先暴露于尼古丁， 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ENDS形式摄入尼古丁的人， 他们从不使用的同伴。尼古丁和烟草成分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得到了解决。的 这项研究的目的是通过评估增加 在雄性动物静脉自我给药模型中， 雌性成年和青春期大鼠。在目标1中，将添加去甲烟碱和新烟草碱， 在目标2中，去甲尼古丁和新烟草碱将添加到成人的自我给药尼古丁中， 青少年。在这两个目标中，我们将评估添加的成分化合物对动机的影响。 尼古丁的价值在每个目标中添加一个组成化合物的效果预计将减少简单的自 因为它们对烟碱乙酰胆碱受体的激动剂作用提供了一定水平的烟碱， 替代。然而，去甲烟碱，而不是新烟草碱，也已被证明具有增强性质， 可能是由于其对α4β2* 受体的相对亲和力大得多。因此，去甲烟碱，而不是新烟草碱， 预期将增强尼古丁的激励价值，通过重复进行渐进比率测量 因为这个附加的加固值。添加成分的不同影响 化合物与尼古丁的关系将为烟草依赖的顽固性提供独特的视角。的确， 目前关于烟草成分对尼古丁滥用倾向的影响的研究， 围绕监管研究的重点是减少烟草中尼古丁含量的影响。目前的研究， 然而，将研究尼古丁与烟草成分化合物对 从这些开始尼古丁摄入的新兴人群的角度来看， 使用ENDS而不是烟草。这种概念上的创新方法， 使用重复的渐进比率计划进行动机评估的操作将使我们能够开始 来解决一个只会随着时间而增长的问题。

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.