Trauth J A, Seidler F J, Slotkin T A
Department of Pharmacology and Cancer Biology, Box 3813 DUMC, Duke University Medical Center, Durham, NC 27710, USA.
Brain Res. 2000 Jun 9;867(1-2):29-39. doi: 10.1016/s0006-8993(00)02208-3.
Nearly all smokers begin tobacco use in adolescence, and approximately 25% of US teenagers are daily smokers. Prenatal nicotine exposure is known to produce brain damage, to alter synaptic function and to cause behavioral anomalies, but little or no work has been done to determine if the adolescent brain is also vulnerable. We examined the effect of adolescent nicotine exposure on indices of cell damage in male and female rats with an infusion paradigm designed to match the plasma levels found in human smokers or in users of the transdermal nicotine patch. Measurements were made of DNA and protein as well as expression of mRNAs encoding genes involved in differentiation and apoptosis (p53, c-fos) in cerebral cortex, midbrain and hippocampus. Following nicotine treatment from postnatal days 30-47.5, changes in macromolecular constituents indicative of cell loss (reduced DNA) and altered cell size (protein/DNA ratio) were seen across all three brain regions. In addition, expression of p53 showed region- and gender-selective alterations consistent with cell damage; c-fos, which is constitutively overexpressed after gestational nicotine exposure, was unaffected with the adolescent treatment paradigm. Although these measures indicate that the fetal brain is more vulnerable to nicotine than is the adolescent brain, the critical period for nicotine-induced developmental neurotoxicity clearly extends into adolescence. Effects on gene expression and cell number, along with resultant or direct effects on synaptic function, may contribute to increased addictive properties and long-term behavioral deficits.
几乎所有吸烟者都是在青少年时期开始使用烟草的，并且美国约25%的青少年是每日吸烟者。已知产前尼古丁暴露会导致脑损伤、改变突触功能并引起行为异常，但对于青少年大脑是否也易受影响，几乎没有或根本没有开展相关研究。我们采用一种灌注模式来研究青少年尼古丁暴露对雄性和雌性大鼠细胞损伤指标的影响，该模式旨在模拟人类吸烟者或经皮尼古丁贴片使用者体内的血浆水平。我们对大脑皮层、中脑和海马体中的DNA、蛋白质以及参与分化和凋亡的基因（p53、c-fos）的mRNA表达进行了测量。在出生后第30至47.5天给予尼古丁处理后，在所有三个脑区均观察到了表明细胞丢失（DNA减少）和细胞大小改变（蛋白质/DNA比率）的大分子成分变化。此外，p53的表达显示出与细胞损伤一致的区域和性别选择性改变；c-fos在孕期尼古丁暴露后会持续过度表达，但在青少年处理模式下未受影响。尽管这些测量结果表明胎儿大脑比青少年大脑更容易受到尼古丁的影响，但尼古丁诱导的发育神经毒性的关键时期显然延伸到了青少年期。对基因表达和细胞数量的影响，以及对突触功能的直接或间接影响，可能会导致成瘾性增加和长期行为缺陷。
