Fetal & Adolescent Nicotine Effects on CNS 5HT Systems

我们开发了啮齿动物的产前尼古丁暴露模型，模拟吸烟者或透皮尼古丁贴片使用者的血浆水平，并证明尼古丁本身是一种神经致畸物，在长时间的明显正常后引起突触功能变化。这些影响针对儿茶酚胺系统，我们有初步数据表明5HT系统也参与其中。大脑的发育一直持续到青春期，几乎所有的吸烟者都是从这个时期开始吸烟的，我们已经建立了一个类似的啮齿动物青少年尼古丁服用模型；儿茶酚胺系统是目标，我们有5HT的初步数据。很明显，一部分吸烟者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高发病率有关。这些发现导致了目前的假设：即尼古丁，在大脑发育的关键时期，改变5HT活性的设定点，在突触前功能水平，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。目的1。确定产前尼古丁暴露如何改变5HT突触功能和行为，这是5HT功能障碍模型中已知的目标。利用神经末梢标记物、5HT转换和急性尼古丁刺激释放5HT的能力评估5HT投射的发展；从出生到成年的研究。通过受体配体结合和腺苷酸环化酶的连接来评估5HT信号转导。目标2。确定尼古丁诱导的5HT功能改变的关键期是否延长至青春期。我们将评估青少年尼古丁治疗和戒断期间5HT突触功能和行为，使用与产前尼古丁模型相同的终点。目标3。确定产前尼古丁暴露是否会改变青少年对尼古丁的反应。产前暴露于尼古丁的动物将接受青少年尼古丁治疗，并评估5HT系统的反应和行为，以及儿茶酚胺能反应和已知受青少年尼古丁影响的尼古丁受体。

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.