Prenatal Exposure to Nicotine Stimulates Neurogenesis of Orexigenic Peptide-Expressing Neurons in Hypothalamus and Amygdala
Prenatal Exposure to Nicotine Stimulates Neurogenesis of Orexigenic Peptide-Expressing Neurons in Hypothalamus and Amygdala
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DOI：
10.1523/jneurosci.5835-12.2013
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发表时间：
2013-08-21
影响因子：
5.3
通讯作者：
Leibowitz, Sarah F.
中科院分区：
文献类型：
--
作者：
Chang, Guo-Qing;Karatayev, Olga;Leibowitz, Sarah F.
动物和临床研究表明，妊娠期接触尼古丁会增加后代摄入尼古丁的倾向，但介导这种行为现象的确切机制尚不清楚。目前在斯普拉格道利大鼠中进行的研究检验了成年动物中促食欲肽系统、脑啡肽（ENK）和食欲素（OX）的可能性，它们在成年动物中受到尼古丁的刺激并促进完成行为，可能在子宫内对尼古丁的刺激作用做出类似的反应，同时产生长期的行为后果。结果表明，妊娠期间低剂量（0.75 或 1.5 mg/kg/d）的尼古丁暴露显着增加断奶前后代下丘脑室旁核和杏仁核中央核 OX 中表达 ENK 的神经元的 mRNA 水平和密度，以及下丘脑外侧下丘脑周围另一种促食欲肽、黑色素浓缩激素的神经元的 mRNA 水平和密度。在没有尼古丁的情况下，这些影响至少持续到青春期。细胞增殖标记物 BrdU 与神经元标记物 NeuN 和肽的共标记显示，产前尼古丁对神经发生（但对胶质细胞生成）以及表达 ENK、OX 或黑色素浓缩激素的新生成神经元的数量有显着的刺激作用。在青春期，后代也表现出显着的行为变化，尼古丁和其他滥用物质、乙醇和高脂肪饮食的摄入量增加，但食物和水的摄入量或体重没有变化。这些发现揭示了促食欲肽神经元在妊娠期间对低尼古丁剂量的显着敏感性，这可能会增加后代在青春期过度消耗滥用物质的倾向。
Animal and clinical studies show that gestational exposure to nicotine increases the propensity of offspring to consume nicotine, but the precise mechanism mediating this behavioral phenomenon is unclear. The present study in Sprague Dawley rats examined the possibility that the orexigenic peptide systems, enkephalin (ENK) and orexin (OX), which are stimulated by nicotine in adult animals and promote consummatory behavior, may be similarly responsive to nicotine's stimulatory effect in utero while having long-term behavioral consequences. The results demonstrated that nicotine exposure during gestation at low doses (0.75 or 1.5 mg/kg/d) significantly increased mRNA levels and density of neurons that express ENK in the hypothalamic paraventricular nucleus and central nucleus of the amygdala, OX, and another orexigenic peptide, melanin-concentrating hormone, in the perifornical lateral hypothalamus in preweanling offspring. These effects persisted in the absence of nicotine, at least until puberty. Colabeling of the cell proliferation marker BrdU with the neuronal marker NeuN and peptides revealed a marked stimulatory effect of prenatal nicotine on neurogenesis, but not gliogenesis, and also on the number of newly generated neurons expressing ENK, OX, or melanin-concentrating hormone. During adolescence, offspring also exhibited significant behavioral changes, increased consumption of nicotine and other substances of abuse, ethanol and a fat-rich diet, with no changes in chow and water intake or body weight. These findings reveal a marked sensitivity during gestation of the orexigenic peptide neurons to low nicotine doses that may increase the offspring's propensity to overconsume substances of abuse during adolescence.