Abstract

Perinatal exposure to prescription opioids pose a critical public health risk. Notably, research has found significant neurodevelopmental and behavioral deficits between in utero (IUO) and postnatal (PNO) oxycodone-exposed offspring but there is a notable gap in knowledge regarding the interaction of these groups to other drug exposure, particularly nicotine exposure. Nicotine’s widespread use represents a ubiquitous clinical interaction that current research does not address. Children often experiment with drugs and risky behavior; therefore, adolescence is a key timepoint to characterize. This study employed an integrated systems approach to investigate escalating nicotine exposure in adolescence and subsequent nicotine withdrawal in the IUO- and PNO-offspring. Western blot analysis found synaptic protein alterations, especially upregulation of synaptophysin in IUO-withdrawal animals. RT-qPCR further validated immune dysfunction in the central nervous system (CNS). Peripheral nicotine metabolism was consistent with increased catabolism of nicotine concerning IUO animals. Lastly, behavioral assays found subtle deficits to withdrawal in nociception and anxiety-like behavior. This study showed, for the first time, the vulnerabilities of PNO- and IUO-exposed groups concerning nicotine use during early adolescence and withdrawal.

Graphical Abstract

中文翻译：

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青少年尼古丁暴露对产前和产后暴露于羟考酮的后代的影响

摘要

围产期接触处方阿片类药物会造成严重的公共健康风险。值得注意的是，研究发现子宫内（IUO）和出生后（PNO）暴露于羟考酮的后代存在显着的神经发育和行为缺陷，但对于这些群体与其他药物暴露（尤其是尼古丁暴露）的相互作用的知识存在显着差距。尼古丁的广泛使用代表了一种普遍存在的临床相互作用，而目前的研究尚未解决这一问题。儿童经常尝试药物和危险行为；因此，青春期是表征的关键时间点。本研究采用综合系统方法来研究 IUO 和 PNO 后代青春期尼古丁暴露的增加以及随后的尼古丁戒断。蛋白质印迹分析发现突触蛋白发生改变，尤其是 IUO 戒断动物中突触素的上调。RT-qPCR 进一步验证了中枢神经系统 (CNS) 的免疫功能障碍。周围尼古丁代谢与 IUO 动物的尼古丁分解代谢增加一致。最后，行为分析发现，在伤害感受和类焦虑行为中存在微妙的退缩缺陷。这项研究首次表明，PNO 和 IUO 暴露群体在青春期早期和戒断期间尼古丁使用方面的脆弱性。