Prenatal Nicotine, Behavioral Teratogenicity and Dopamine

描述（由申请人提供）：即使在调整了其他可能的遗传和环境混杂因素后，暴露于产前烟草烟雾的儿童的神经心理发育也经常受损。虽然烟草烟雾中导致发育改变的病原体尚不清楚，但从动物研究中积累的证据表明，尼古丁可能起着至关重要的作用。然而，在大多数动物研究中，尼古丁已被急性给药给幼鼠，导致严重的胎儿缺氧和应激激素水平升高，这可能有助于不利的胎儿环境。我们之前的研究表明，口服尼古丁暴露是一种无压力的有效方法，可以给怀孕的老鼠提供尼古丁。给怀孕的老鼠口服尼古丁会导致后代的基线行为和对尼古丁的敏感性发生持久的、性别依赖的变化。在本提案中，我们将研究一种可能的神经化学机制，该机制可能是发育性尼古丁暴露产生的行为致畸性的基础。我们建议对产前尼古丁给药后多巴胺能和尼古丁胆碱能神经元系统结构/功能的变化进行全面和系统的评估。这一提议的基本假设是，产前尼古丁暴露改变了发育中的小鼠神经系统中凋亡细胞死亡的时间和解剖模式。抑制中枢神经系统凋亡细胞的死亡可能导致永久性的分子、细胞或神经化学变化，使动物对药物的敏感性和/或对药物寻找和复发的易感性发生改变。这些研究将全面评估产前尼古丁暴露后胆碱能和多巴胺能神经传递的变化。鉴于有一致的证据表明多巴胺（DA）神经传递的增强可能对尼古丁强化/成瘾很重要，我们认为多巴胺能功能的评估是机制研究中最相关的目标，以揭示尼古丁诱导的行为致畸的原因。这些研究与公众健康有关，因为尼古丁替代疗法通常用于希望戒烟的孕妇。我们认为尼古丁在子宫内接触烟草烟雾的负面结果中起着重要作用。

DESCRIPTION (provided by applicant): Neuropsychological development is frequently impaired in children exposed to prenatal tobacco smoke, even after adjusting for other possible genetic and environmental confounds. Although the causative agents in tobacco smoke that lead to altered development are not known, accumulating evidence from animal studies suggests that nicotine may play a crucial role. However, in most animal studies nicotine has been administered acutely to naive dams, leading to significant fetal hypoxia and increased levels of stress hormones, which could contribute to an unfavorable fetal environment. Our previous studies have shown that oral nicotine exposure is a stress free and effective method for delivery of nicotine to pregnant mice. Oral nicotine delivery to pregnant mice causes persistent, gender-dependent changes in baseline behavior and sensitivity to nicotine in the progeny. In this proposal we will study one possible neurochemical mechanism that may underlie behavioral teratogenicity produced by developmental nicotine exposure. We propose a thorough and systematic evaluation of changes in structure/function of dopaminergic and nicotinic cholinergic neuronal systems following prenatal nicotine administration. The underlying hypothesis of this proposal is that prenatal nicotine exposure changes the temporal and anatomical patterns of apoptotic cell death in the developing mouse nervous system. Inhibition of apoptotic cell death in the CNS may cause permanent molecular, cellular or neurochemical changes that predispose animals to have altered sensitivity to drugs and/or susceptibility to drug seeking and relapse. These studies will provide a thorough assessment of changes in cholinergic and dopaminergic neurotransmission following prenatal nicotine exposure. In light of consistent evidence that enhancement of dopamine (DA) neurotransmission may be important for nicotine reinforcement/addiction, we believe that evaluation of dopaminergic function is the most relevant target for mechanistic studies to unravel the causes of nicotine induced behavioral teratogenicity. These studies are relevant to public health since nicotine replacement therapy is commonly prescribed for women that are pregnant and wish to stop smoking tobacco. We believe that nicotine plays a significant role in the negative outcomes that have been frequently associated with in utero tobacco smoke exposure.