The role of non-nicotine tobacco smoke constituents in withdrawal and craving

 烟草使用仍然是美国过早死亡的主要原因，30%的癌症死亡和18%的所有死亡直接归因于吸烟。开始使用烟草主要发生在青春期，年轻人的吸烟率达到高峰。虽然烟草烟雾含有超过8000种成分，但大多数用于测试戒烟疗法的动物模型都集中在成年男性中尼古丁的作用上。对烟草中的非尼古丁成分和首次使用年龄缺乏关注可能是目前戒烟药物成功率低的原因。由于临床数据显示烟草依赖的性别差异，研究女性也很重要。我们的研究小组是唯一一个研究非尼古丁成分对青少年和成人尼古丁作用的影响的研究小组。我们已经证明，成年和青少年大鼠将自我管理香烟烟雾提取物（CSE），通过鼓泡香烟烟雾通过盐溶液。在成年雄性大鼠中，CSE比单独使用同等剂量的尼古丁更能强化，自我施用CSE的动物比单独使用尼古丁的动物对压力和尼古丁诱导的药物寻求行为的恢复更敏感。我们的数据还表明，与尼古丁相比，青少年和成人在停止长期CSE给药后表现出更多的躯体戒断。这些研究结果表明，在其他烟草烟雾成分存在的情况下评估尼古丁的影响非常重要。本申请的目的是检查已经用CSE长期治疗的动物中增强的戒断和药物寻求行为的潜在机制。除了评估青少年和成年男性外，我们还将启动CSE暴露对女性影响的首批研究。该提案的具体目的包括：1）比较青春期和成年雄性大鼠长期暴露于尼古丁和CSE后的躯体和情感戒断症状。我们将进一步检验以下假设，即单胺氧化酶抑制、烟碱乙酰胆碱和/或κ阿片受体功能增强是我们在成年和青少年男性中观察到的慢性CSE治疗停止后增加的躯体戒断的基础; 2）青少年和成年男性中尼古丁和CSE寻求行为的压力诱导恢复的比较，和评估α 3 β 4烟碱受体在介导药物渴求中的作用; 3）在女性中建立获得CSE自我给药和单独使用等效剂量尼古丁的剂量-反应关系。该方法具有创新性，其目的是通过检查烟草烟雾含水组分的综合影响来弥合人类和动物研究之间的差距。拟议的研究是重要的，因为它提供了一个更全面的方法来确定烟草依赖的神经机制的第一步，并可能导致改进的戒烟临床疗法的发展。

 DESCRIPTION (provided by applicant): Tobacco use remains a major cause of premature death in the United States, with 30% of cancer deaths and 18% of all deaths directly attributable to smoking. Initiation of tobacco use occurs primarily during adolescence, with smoking rates peaking in young adults. Although tobacco smoke contains over 8000 constituents, most animal models used for testing smoking cessation therapies focus on the effects of nicotine alone in adult males. This lack of attention to both the non-nicotine constituents of tobacco and the age of first use may account for the low success rate of current tobacco cessation medications. With clinical data showing sex differences in tobacco dependence, it is also important to study females. Our group has been one of the only ones to examine the impact of non-nicotine constituents on nicotine actions in both adolescents and adults. We have shown that adult and adolescent rats will self-administer cigarette smoke extract (CSE), made by bubbling cigarette smoke through saline solution. CSE is more reinforcing in adult male rats than equivalent doses of nicotine alone, and animals that self-administered CSE are more sensitive to both stress- and nicotine-induced reinstatement of drug-seeking behavior than animals that worked for nicotine alone. Our data also suggest that both adolescents and adults exhibit more somatic withdrawal upon cessation of chronic CSE administration than nicotine. These findings indicate the importance of assessing the effects of nicotine in the presence of other tobacco smoke constituents. The objective of the current application is to examine mechanisms underlying enhanced withdrawal and drug-seeking behavior in animals that have been chronically treated with CSE. In addition to evaluating adolescent and adult males, we will initiate one of the first studies of the impact of CSE exposure in females. The specific aims of the proposal include: 1) Comparison of somatic and affective withdrawal symptoms following chronic nicotine and CSE exposure in adolescent and adult rats of both sexes. We will further test the hypotheses that monoamine oxidase inhibition, enhanced nicotinic acetylcholine and/or kappa opioid receptor function underlie the increased somatic withdrawal that we have observed following cessation of chronic CSE treatment in adult and adolescent males; 2) Comparison of stress-induced reinstatement of nicotine- and CSE-seeking behavior in adolescent and adult males, and assessment of the role of a3ß4 nicotinic receptors in mediating drug craving; 3) Establish a dose-response relationship for acquisition of self-administration of CSE, and equivalent doses of nicotine alone, in females. The approach is innovative in that it aims to bridge the gap between human and animal studies by examining the combined impact of tobacco smoke aqueous components. The proposed research is significant in that it provides an initial step towards a more comprehensive approach to determining neural mechanisms underlying tobacco dependence, and may result in the development of improved clinical therapies for smoking cessation.