Fetal & Adolescent Nicotine Effects on CNS 5HT Systems

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• 批准号: 6515906
• 负责人: THEODORE A SLOTKIN
• 金额: $ 23.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6515906
• 关键词: adenylate cyclase; biological signal transduction; catecholamines; disease /disorder model; embryo /fetus toxicology; laboratory rat; neurophysiology; neurotoxicology; nicotine; nicotine replacement; nicotinic receptors; receptor binding; serotonin; tobacco

We have developed rodent models of prenatal nicotine exposure that simulate the plasma levels found in smokers or in users of the transdermal nicotine patch, and have demonstrated that nicotine itself is a neuroteratogen that elicits synaptic functional changes appearing after an extended period of apparent normality. These effects target catecholamine systems and we have preliminary data indicating involvement of 5HT systems as well. Brain development continues into adolescence, the period in which nearly all smokers begin smoking, and we have developed a comparable rodent model of adolescent nicotine administration; again, catecholamine systems are targeted and we have preliminary data for 5HT. It is clear that a subset of smokers are using tobacco to self-medicate for depression; additionally, adolescent smoking is associated with higher incidence of subsequent depression. These findings lead to the current hypothesis: namely that nicotine, during a critical period of brain development, alters the set-point for 5HT activity, at the level of presynaptic function, at receptor signal transduction cascades, or both. This will be pursued in fetal and adolescent nicotine exposure models, utilizing neurochemical, cell signaling, and behavioral approaches. Aim 1. To determine how prenatal nicotine exposure alters 5HT synaptic function and behaviors known to be targeted in models of 5HT dysfunction. Evaluate development of 5HT projections, using nerve terminal markers, 5HT turnover, and the ability of acute nicotine challenge to release 5HT; studies conducted from birth to adulthood. 5HT signal transduction assessed with receptor ligand binding and linkages to adenylyl cyclase. Aim 2. To determine whether the critical period for nicotine- induced alterations in the programming of 5HT function extends into adolescence. We will assess 5HT synaptic function and behaviors during adolescent nicotine treatment and withdrawal, using the same endpoints as studied with the prenatal nicotine model. Aim 3. To determine whether prenatal nicotine exposure alters the response to subsequent adolescent nicotine administration. Animals exposed prenatally to nicotine will receive adolescent nicotine treatment and the response of 5HT systems and behavior will be assessed, along with catecholaminergic responses and nicotinic receptors known to be affected by adolescent nicotine.

我们开发了产前尼古丁暴露的啮齿动物模型，模拟吸烟者或尼古丁透皮贴剂使用者的血浆水平，并证明尼古丁本身是一种神经致畸剂，可在长时间明显正常后诱发突触功能变化。 这些影响的目标是儿茶酚胺系统，我们有初步的数据表明参与5 HT系统以及。 大脑发育持续到青春期，几乎所有吸烟者开始吸烟的时期，我们已经开发了一个可比较的青少年尼古丁给药啮齿动物模型;再次，儿茶酚胺系统是目标，我们有初步的数据5 HT。 很明显，吸烟者的一个子集正在使用烟草来自我治疗抑郁症;此外，青少年吸烟与随后抑郁症的发病率较高有关。 这些发现导致目前的假设：即尼古丁，在大脑发育的关键时期，改变了5 HT活性的设定点，在突触前功能的水平，在受体信号转导级联，或两者兼而有之。 这将在胎儿和青少年尼古丁暴露模型中进行，利用神经化学，细胞信号和行为方法。 目标1.确定产前尼古丁暴露如何改变已知在5 HT功能障碍模型中靶向的5 HT突触功能和行为。使用神经末梢标记物、5-HT周转率和急性尼古丁激发释放5-HT的能力评价5-HT投射的发展;从出生到成年进行的研究。 用受体配体结合和与腺苷酸环化酶的连接评估5 HT信号转导。目标二。确定尼古丁诱导的5 HT功能编程改变的关键期是否延伸到青春期。 我们将使用与产前尼古丁模型研究相同的终点，评估青少年尼古丁治疗和戒断期间的5 HT突触功能和行为。目标3.确定产前尼古丁暴露是否会改变对随后青少年尼古丁给药的反应。产前暴露于尼古丁的动物将接受青春期尼古丁治疗，并评估5 HT系统和行为的反应，沿着已知受青春期尼古丁影响的儿茶酚胺能反应和烟碱受体。