Fetal nicotine or cocaine exposure: which one is worse?
Fetal nicotine or cocaine exposure: which one is worse?
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发表时间：
1998-06
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通讯作者：
T. Slotkin
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作者：
T. Slotkin
尽管有广泛的负面宣传，但美国约25%的孕妇仍在使用烟草，使包括可卡因在内的非法药物滥用相形见绌。母亲吸烟的社会代价最容易出现在体重不足的新生儿身上，表现为围产期发病率、死亡率和婴儿猝死综合症的高发生率，以及学习和行为的持续缺陷。我们设计了尼古丁暴露的动物模型，以证明尼古丁本身是一种神经畸形物，从而在烟草暴露和不良围产期结果之间提供了因果联系。特别是，尼古丁输注范例，就像人类使用的透皮贴片一样，产生不与烟草其他成分或间歇性缺氧缺血性侮辱相混淆的药物暴露，使人们能够机械地剖析尼古丁在胎儿大脑损伤中所起的作用。尼古丁针对胎儿大脑中的特定神经递质受体，引发细胞增殖和分化的异常，导致细胞数量不足，最终改变突触活动。由于胆碱能和儿茶酚胺能系统的密切调控联系，尼古丁的不良反应涉及多个递质途径，不仅影响胎儿大脑的即刻发育事件，而且还影响突触能力的最终编程。因此，在明显正常的较长时间后，缺陷可能会出现，导致认知和学习缺陷，出现在童年或青春期。在外周自主神经通路中也会发生类似的变化，导致对缺氧引起的脑损伤、围产期死亡和婴儿猝死的易感性增加。明确胎儿尼古丁暴露引起的神经行为损害的受体驱动机制，为妊娠期间尼古丁替代疗法的戒烟决策提供了合理的基础。与尼古丁的影响相反，怀孕期间使用强效可卡因的动物模型显示出更有限的影响范围，这反映了两种药物在药代动力学和药效学方面的差异。值得注意的是，尽管可卡因和尼古丁一样，也是针对细胞复制的，但它的影响是短暂的，允许在两次剂量之间进行恢复，因此最终的后果要轻得多。在某种程度上，可卡因对大脑发育的影响类似于尼古丁，因为两者都有心血管活动(血管收缩)，在某些情况下，会引发胎儿缺氧缺血。鉴于几乎所有吸食强效可卡因的人都吸烟的事实，可能很难发现可卡因对发育的具体影响。尽管科学家和公众仍然比尼古丁或烟草使用更多地关注胎儿可卡因的影响，但将重点转向烟草可能会对人类健康产生不成比例的更大影响。
Despite extensive adverse publicity, tobacco use continues in approximately 25% of all pregnancies in the United States, overshadowing illicit drugs of abuse, including cocaine. The societal cost of maternal smoking is seen most readily in underweight newborns, in high rates of perinatal morbidity, mortality and Sudden Infant Death Syndrome and in persistent deficits in learning and behavior. We have designed animal models of nicotine exposure to prove that nicotine itself is a neuroteratogen, thus providing a causative link between tobacco exposure and adverse perinatal outcomes. In particular, nicotine infusion paradigms that, like the transdermal patch used in man, produce drug exposure without the confounds of other components of tobacco or of episodic hypoxic-ischemic insult, have enabled a mechanistic dissection of the role played by nicotine in fetal brain damage. Nicotine targets specific neurotransmitter receptors in the fetal brain, eliciting abnormalities of cell proliferation and differentiation, leading to shortfalls in the number of cells and eventually to altered synaptic activity. Because of the close regulatory association of cholinergic and catecholaminergic systems, adverse effects of nicotine involve multiple transmitter pathways and influence not only the immediate developmental events in fetal brain, but also the eventual programming of synaptic competence. Accordingly, defects may appear after a prolonged period of apparent normality, leading to cognitive and learning defects that appear in childhood or adolescence. Comparable alterations occur in peripheral autonomic pathways, leading to increased susceptibility to hypoxia-induced brain damage, perinatal mortality and Sudden Infant Death. Identifying the receptor-driven mechanisms that underlie the neurobehavioral damage caused by fetal nicotine exposure provides a rational basis for decisions about nicotine substitution therapy for smoking cessation in pregnancy. In contrast to the effects of nicotine, animal models of crack cocaine use in pregnancy indicate a more restricted spectrum of effects, a reflection of differences both in pharmacokinetics and pharmacodynamics of the two drugs. Notably, although cocaine, like nicotine, also targets cell replication, its effects are short-lived, permitting recovery to occur in between doses, so that the eventual consequences are much less severe. To some extent, the effects of cocaine on brain development resemble those of nicotine because the two share cardiovascular actions (vasoconstriction) that, under some circumstances, elicit fetal hypoxia-ischemia. In light of the fact that nearly all crack cocaine users smoke cigarettes, the identification of specific developmental effects of cocaine may prove difficult to detect. Although scientists and the public continue to pay far more attention to fetal cocaine effects than to those of nicotine or tobacco use, a change of focus to concentrate on tobacco could have a disproportionately larger impact on human health.