Animal Models for Risk Factors for Smoking Relapse

许多现在的吸烟者表现出几个危险因素，使戒烟变得更加困难。我们建议研究危险因素如何可能导致再次吸烟的生物学基础。戒烟治疗失败的一些预测因素包括体重担忧、酗酒和女性性别。 这项建议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，并将重点放在神经元烟碱型乙酰胆碱受体(NAChRs)如何影响与这些风险因素相关的行为和生化反应。这些实验将利用正常啮齿动物的药理学研究，以及缺乏nAChR Beta2亚基的小鼠的实验，在特定脑区选择性表达这些nAChR的转基因品系，以及缺乏先前产生的神经肽CART、甘丙素和NPY的基因敲除小鼠。这个项目的目标是：1)跟进先前的研究，通过使用病毒载体和局部输注策略来确定尼古丁治疗影响的第二信使途径，确定这些途径的功能效应 目的：研究尼古丁成瘾相关行为的分子变化；2)确定尼古丁治疗后行为模式改变的正常小鼠和大鼠，以及缺乏下丘脑肽的正常小鼠和大鼠中尼古丁的摄入量、下丘脑肽的表达和食欲行为的关系(这些参数也将被研究纳曲酮对这些参数的影响)；3)确定这些行为和神经化学影响中的性别差异；4)确定慢性酒精和尼古丁治疗对食欲行为中生化和行为反应的并行和独立影响。这些实验将有助于为抗拒当前戒烟方法的吸烟者设计新的治疗策略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.