Prenatal Nicotine, Behavioral Teratogenicity and Dopamine

产前尼古丁、行为致畸性和多巴胺

• 批准号: 7197788
• 负责人: JAMES R PAULY
• 金额: $ 18.31万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7197788
• 关键词: dopamine; nicotine

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.

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状态后，暴露于产前烟草烟雾的儿童中，神经心理学发展也经常受到损害。尽管烟草烟雾中导致发育发生变化的因果剂尚不清楚，但从动物研究中积累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，尼古丁已被敏锐地给予天真的大坝，从而导致胎儿缺氧明显的低氧和增加的压力激素水平，这可能导致不利的胎儿环境。我们以前的研究表明，口服尼古丁的暴露是无应力有效的方法，可将尼古丁递送到怀孕小鼠。口服尼古丁向怀孕小鼠递送会导致基线行为的持续性，性别依赖性变化以及对后代中尼古丁的敏感性。在此提案中，我们将研究一种可能是由发育性尼古丁暴露产生的行为致致致造性的可能的神经化学机制。我们提出了对产前尼古丁给药后多巴胺能和烟碱能神经元系统结构/功能变化的彻底评估。该提议的基本假设是，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。中枢神经系统中凋亡细胞死亡的抑制可能会引起永久性分子，细胞或神经化学变化，使动物容易改变对药物的敏感性和/或对寻求药物寻求和复发的敏感性。这些研究将对产前尼古丁暴露后的胆碱能和多巴胺能神经传递的变化进行彻底评估。鉴于一致的证据表明，增强多巴胺（DA）神经传递对尼古丁的增强/成瘾可能很重要，我们认为评估多巴胺能功能是机械研究的最相关的目标，即揭示尼古丁诱导的行为诱导行为性致病性的原因。这些研究与公共卫生有关，因为尼古丁替代疗法通常是针对怀孕并希望停止吸烟的妇女的。我们认为，尼古丁在子宫烟草烟雾中经常相关的负面结果中起着重要作用。