MOUSE MODELS FOR NICOTINE'S INTERACTION WITH STRESS

描述（由申请人提供）：在本申请中，我们将通过研究几种小鼠模型的行为、自主神经反应、激素和神经递质水平来研究慢性应激和尼古丁之间的相互作用。这一提议源于一项发现，即吸烟者经常报告香烟有抗焦虑作用，而与压力相关的疾病，如抑郁症、创伤后应激综合症和焦虑，往往与长期使用尼古丁有关。尼古丁的影响可能取决于其在应激相关神经回路中激活和脱敏尼古丁乙酰胆碱受体（nAChRs）的能力。尼古丁的基本作用，反过来，依赖于nachr的亚基组成来调节这些神经回路。一个相关的现象是，长期暴露在压力下会在大脑区域产生神经适应，这些区域与尼古丁的奖励效应有关。为了确定哪些nAChR亚型在应激和尼古丁作用之间的相互作用中起重要作用，我们将缺乏一个或多个nAChR亚基组合的nAChR突变小鼠暴露于慢性应激环境中。我们的实验将利用我们和其他人在nAChR突变小鼠中报道的焦虑相关表型。该应用程序还将解决压力/尼古丁相互作用中的性别差异。性别在压力整合和压力相关的情感疾病状态中起主要作用。我们将通过在切除卵巢和睾丸的动物身上进行实验来研究与性别相关的机制。通过分析单独或联合缺乏孕激素受体A和B的小鼠，我们将特别关注孕激素在应激生理机制中的作用。该提案将首先检查慢性应激对nAChR突变小鼠及其野生型幼崽的影响。另外两个主要目的是研究压力和尼古丁之间的相互作用。第二个目标是研究慢性压力如何影响对急性剂量尼古丁的反应。第三个目标是检查慢性尼古丁产生的行为和生理表现，无论是否同时暴露于压力下。我们的体内研究将结合行为测试、遥测和血浆应激激素水平的测量。体外研究将使用原位杂交、放射自显影和免疫组织化学技术。

DESCRIPTION (provided by applicant): In this application we will examine the interaction between chronic stress and nicotine by studying behavior, autonomic responses, and hormone and neurotransmitter levels in several mouse models. This proposal arises from the finding that smokers often report an anxiolytic effect of cigarettes, and stress-related disorders such as depression, posttraumatic stress syndrome, and anxiety are often associated with chronic nicotine use. The influence of nicotine might depend on its ability to both activate and desensitize nicotinic acetylcholine receptors (nAChRs) in stress-related neural circuits. That basic action of nicotine, in turn, depends on the subunit composition of nAChRs that modulate those neural circuits. A related phenomenon is that chronic exposure to stress produces neural adaptations in brain regions that are associated with the rewarding effects of nicotine. To determine which nAChR subtypes are important for the interaction between stress and nicotine's actions, we will expose nAChR mutant mice lacking one or combinations of nAChR subunits to chronic stress. Our experiments will capitalize on the anxiety-related phenotypes that we and others have reported in nAChR mutant mice. The application also will address gender differences in the stress/nicotine interaction. Gender plays a major role in stress integration and stress-related affective disease states. We will investigate gender-related mechanisms by performing our experiments in ovariectomized and orchiectomized animals. Particular attention will be paid to the role of progesterone in the physiological mechanisms underlying stress by analyzing mice lacking the progesterone receptors A and B alone or in combination. The proposal will begin by examining the effects of chronic stress on nAChR mutant mice and their wild-type littermates. The other two main aims will examine the interaction between stress and nicotine. The second aim will examine how chronic stress affects the response to acute doses of nicotine. The third aim will examine the behavioral and physiological manifestations produced by chronic nicotine with and without concomitant exposure to stress. Our in vivo studies will combine behavioral testing with telemetry and the measurement of plasma levels of stress hormones. The in vitro studies will use in situ hybridization, autoradiography, and immunohistochemistry techniques.