Animal Models for Risk Factors for Smoking Relapse

许多目前的吸烟者表现出几个风险因素，使戒烟更加困难。我们建议研究风险因素如何导致复吸的生物学基础。戒烟治疗失败的一些预测因素包括体重问题，大量饮酒和女性性别。 该提案将使用动物模型来确定尼古丁如何影响与这些风险因素相关的生物过程，并将重点关注神经元烟碱乙酰胆碱受体（nAChR）如何影响与这些风险因素相关的行为和生化反应。这些实验将利用在正常啮齿动物中的药理学研究以及用缺乏nAChR的β 2亚基的小鼠、在特定脑区域中具有这些nAChR的选择性表达的转基因系和缺乏先前已经产生的神经肽CART、甘丙肽和NPY的敲除小鼠进行的实验。本项目的目的是：1）通过使用病毒载体和局部输注策略，跟踪先前确定尼古丁治疗影响的第二信使途径的研究， 尼古丁成瘾相关行为的分子变化; 2）确定尼古丁、食物摄入、下丘脑肽表达与尼古丁处理后行为范式的正常小鼠和大鼠以及缺乏进食相关下丘脑肽的敲除小鼠的食欲行为之间的关系（也将研究纳洛酮对这些参数的影响）; 3）确定这些行为和神经化学效应的性别差异; 4）并确定慢性乙醇和尼古丁处理对食欲行为中的生化和行为反应的同时和独立影响。这些实验将有助于为设计新的策略来治疗对当前戒烟方法有抵抗力的吸烟者提供必要的科学背景。

Many current smokers show several risk factors that make smoking cessation more difficult. We propose to study the biological basis underlying how risk factors might lead to relapse to smoking. Some predictors of treatment failure for smoking cessation include weight concerns, heavy alcohol use, and female gender. This proposal will use animal models to determine how nicotine affects biological processes related to these risk factors, and will focus on how neuronal nicotinic acetylcholine receptors (nAChRs) can affect behavioral and biochemical responses related to these risk factors. These experiments will make use of pharmacological studies in normal rodents as well as experiments with mice lacking the beta2 subunit of the nAChR, transgenic lines with selective expression of these nAChRs in particular brain regions and knockout mice lacking the neuropeptides CART, galanin and NPY which have previously been generated. The aims of this project are: 1) to follow up on previous studies identifying second messenger pathways affected by nicotine treatment by using viral vector and local infusion strategies, identifying functional effects of these molecular changes on behaviors related to nicotine addiction; 2) to determine the relationship between nicotine, food intake, expression of hypothalamic peptides and appetitive behaviors in normal mice and rats undergoing behavioral paradigms following nicotine treatment, and in knockout mice lacking hypothalamic peptides related to feeding (the effect of naltrexone on these parameters will also be investigated); 3) to identify sex differences in these behavioral and neurochemical effects; 4) and to determine the concurrent and independent effects of chronic ethanol and nicotine treatment on biochemical and behavioral responses in appetitive behaviors. These experiments will contribute to the scientific background necessary for designing new strategies for treatment of smokers resistant to current cessation methods.