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

非尼古丁烟草烟雾成分在戒断和渴望中的作用

• 批准号: 9069787
• 负责人: FRANCES M. LESLIE
• 金额: $ 33.5万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069787
• 关键词: Accounting; Acetylcholine; Adolescence; Adolescent; Adult; Affective; Age; Agonist; Animal Model; Animals; Attention; Behavior; Behavioral; Cessation of life; Chronic; Clinical; Clinical Data; Corticotropin-Releasing Hormone Receptors; Data; Dependence; Development; Dose; Drug Addiction; Effectiveness; Evaluation; Exhibits; Experimental Models; Female; Female Adolescents; Foundations; Future; Habits; Health; Human; Lead; Male Adolescents; Malignant Neoplasms; Mediating; Modeling; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Nicotine; Nicotinic Receptors; Opioid Receptor; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Policies; Pre-Clinical Model; Rattus; Regulation; Research; Role; Saline; Self Administration; Self-Administered; Sex Characteristics; Smoker; Smoking; Stimulus; Stress; Study models; Testing; Tobacco; Tobacco Dependence; Tobacco Use Cessation; Tobacco smoke; Tobacco use; United States; Withdrawal; Withdrawal Symptom; Work; aqueous; cigarette smoking; craving; drug craving; drug seeking behavior; grasp; improved; innovation; male; mature animal; neuromechanism; preclinical study; premature; receptor function; research study; response; sex; smoking cessation; success; young adult

 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.

 描述（由申请人提供）：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% 的死亡直接归因于吸烟。开始吸烟主要发生在青少年时期，吸烟率较高。尽管烟草烟雾含有超过 8000 种成分，但大多数用于测试戒烟疗法的动物模型只关注尼古丁对成年男性的影响。烟草中的非尼古丁成分和首次使用的年龄可能是目前戒烟药物成功率较低的原因，临床数据显示烟草依赖存在性别差异，因此我们的研究小组也是其中之一。唯一研究非尼古丁成分对青少年和成人尼古丁作用的影响我们已经证明，成年和青少年大鼠会自行服用香烟烟雾提取物（CSE），这种提取物是通过盐水溶液冒泡香烟烟雾而制成的。在成年雄性大鼠中，CSE 比单独服用同等剂量的尼古丁更有效，并且与单独服用尼古丁的动物相比，自我施用 CSE 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。表明青少年和成人在停止长期服用 CSE 后表现出比尼古丁更多的躯体戒断症状。这些发现表明评估尼古丁在其他烟草烟雾成分存在下的影响的重要性。目前的应用是检查长期接受 CSE 治疗的动物中戒断和药物寻求行为增强的机制。除了评估青少年和成年雄性之外，我们还将启动第一项关于 CSE 暴露对雌性的影响的研究。该提案的具体目标包括： 1) 比较青少年和成年雌性大鼠慢性尼古丁和 CSE 暴露后的躯体和情感戒断症状 我们将进一步测试单胺氧化酶抑制、烟碱增强的假设。乙酰胆碱和/或 kappa 阿片受体功能是我们在成年和青少年男性停止慢性 CSE 治疗后观察到的躯体戒断增加的基础。 2) 青少年和成年男性压力诱导的尼古丁和 CSE 寻求行为恢复的比较； ，并评估a3ß4烟碱受体在介导药物渴望中的作用；3)建立自我给药的剂量-反应关系；该方法的创新之处在于，它旨在通过检查烟草烟雾含水成分的综合影响来弥合人类和动物研究之间的差距。迈向更全面的方法来确定烟草依赖背后的神经机制的第一步，并可能导致改进戒烟临床疗法的发展。