MOUSE MODELS FOR NICOTINE'S INTERACTION WITH STRESS

描述(申请人提供)：在这项申请中，我们将通过研究几个小鼠模型的行为、自主神经反应以及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。这一建议源于一项发现，即吸烟者经常报告香烟具有缓解焦虑的作用，而与压力相关的疾病，如抑郁症、创伤后应激综合征和焦虑症，往往与长期使用尼古丁有关。尼古丁的影响可能取决于其激活和脱敏应激相关神经回路中的烟碱型乙酰胆碱受体(NAChRs)的能力。尼古丁的基本作用反过来又取决于调节这些神经回路的nAChRs的亚单位组成。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，这与尼古丁的奖赏效应有关。为了确定哪些nAChR亚型对于压力和尼古丁的作用之间的相互作用是重要的，我们将把缺乏一个或多个nAChR亚基的nAChR突变小鼠暴露在慢性应激中。我们的实验将利用我们和其他人在nAChR突变小鼠中报告的与焦虑相关的表型。该应用程序还将解决压力/尼古丁相互作用中的性别差异。性别在应激整合和应激相关情感性疾病状态中起着重要作用。我们将通过在去卵巢和去的动物身上进行实验来研究性别相关的机制。通过分析缺乏黄体酮受体A和B的小鼠，特别注意黄体酮在应激的生理机制中的作用。该提案将从检查慢性应激对nAChR突变小鼠及其野生型小鼠的影响开始。另外两个主要目标将研究压力和尼古丁之间的相互作用。第二个目标将研究慢性压力如何影响对急性剂量尼古丁的反应。第三个目标将研究慢性尼古丁在伴随和不伴随压力暴露的情况下产生的行为和生理表现。我们的活体研究将把行为测试与遥测和测量血浆应激激素水平相结合。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.