NICOTINIC CHOLINERGIC SYSTEMS IN MUTANT MICE

在美国，烟草使用是一个主要的健康问题，每年有超过40万人死亡和500亿美元的医疗费用直接归因于吸烟(Eping-Jordan等人，1998年)。青少年每年抽11亿包香烟，未来的医疗费用将超过2000亿美元(Woolf，1997)。尼古丁是烟草中导致上瘾的主要成分，但其潜在机制尚不清楚。该计划项目申请采取多层次的方法来了解尼古丁胆碱能系统以及尼古丁对突触事件、心血管功能和行为的影响。总体而言，该计划将调查这一假设，即不同的烟碱乙酰胆碱受体(NAChR)亚单位在神经系统中有助于烟碱胆碱能功能的个体属性中具有特殊的重要性。在生产nAChR亚单位突变小鼠的过程中，出现了三个项目。由博德特博士领导的小鼠核心已经培育出缺乏Alpha3、Alpha5、Alpha7、Beta3或Beta4的空白小鼠，以及一只表达Alpha7 L247T突变的小鼠，该突变减少了脱敏反应。由阿姆斯特朗博士领导的形态核心将对每一只突变小鼠进行系统的解剖学和组织学筛查，并将根据需要进行进一步的形态研究。这三个项目离不开突变小鼠，突变小鼠是每项研究中使用的基本工具。丹尼项目将直接研究改变的nAChRs和尼古丁活动的突触基础。这项工作旨在提供基本的生物物理和突触信息，这些信息将有助于解释所有项目的结果。德·比亚西项目将使用无线电遥测技术来检查尼古丁对自主神经系统和心血管功能的影响。其中一个具体的目标是了解为什么血压升高时比心率增加时更快地产生对尼古丁的耐受性。佩勒项目将使用一系列行为测试来检查突变小鼠，目的是了解nAChR亚单位如何调节对尼古丁的敏感性和耐受性的发展。

Tobacco use is a major health problem in the United States, where over 400,00 deaths and $50 billion in medical costs yearly are directly attributed to smoking (Epping-Jordan et al., 1998). Teenagers smoke 1.1 billion packs of cigarettes annually and will account for more than $200 billion in future health care costs (Woolf, 1997). Nicotine is the major component of tobacco that leads to addiction, but the underlying mechanisms remain unclear. This Program Project application takes a multi-level approach to understand nicotinic cholinergic systems and nicotine's effect on synaptic events, cardiovascular function, and behavior. Overall the Program will investigate the hypothesis that different nicotinic acetylcholine receptor (nAChR) subunits have special importance in the individual properties that contribute to nicotinic cholinergic functions in the nervous system. Three Projects have arisen from the production of mutant mice for nAChR subunits. The Mouse Core, headed by Dr. Beaudet, has already produced null mice lacking alpha3, alpha5, alpha7, beta3, or beta 4, and a mouse expressing in alpha7 L247T mutation that diminishes desensitization. The Morphology Core, headed by Dr. Armstrong, will do a systematic anatomical and histological screen of each mutant mouse, and will pursue further morphological investigations as warranted. The three Projects could not exist without the mutant mice, which are the fundamental tool used in each investigation. The Dani Project will directly study the altered nAChRs and the synaptic basis for nicotine's actions. The work is intended to provide basic biophysical and synaptic information that will be helpful when interpreting the results from all of the Projects. The De Biasi Project will use radio-telemetry to examine the effects of nicotine on the autonomic nervous system and cardiovascular functions. Among the specific goals is to understand how tolerance to nicotine develops more rapidly for increases in blood pressure than for increases in heart rate. The Paylor Project will use a battery of behavioral tests to examine the mutant mice with the aim of understanding how nAChR subunits regulate the sensitivity to nicotine and the development of tolerance.