Institute for Behavioral Genetics, University of Colorado, Boulder, United States; Department of Integrative Physiology, University of Colorado, Boulder, United States.
Institute for Behavioral Genetics, University of Colorado, Boulder, United States.
Neuropharmacology. 2019 May 1;149:66-82. doi: 10.1016/j.neuropharm.2019.02.006. Epub 2019 Feb 8.
Maternal smoking during pregnancy, a form of developmental nicotine exposure (DNE), is associated with increased nicotine use and neurodevelopmental disorders such as ADHD in children. Here, we characterize the behavioral, rhythmometric, neuropharmacological, and epigenetic consequences of DNE in the F1 (first) and F2 (second) generation adolescent offspring of mice exposed to nicotine prior to and throughout breeding. We assessed the effects of passive oral methylphenidate (MPH) administration and voluntary nicotine consumption on home cage activity rhythms and activity and risk-taking behaviors in the open field. Results imply a multigenerational predisposition to nicotine consumption in DNE mice and demonstrate ADHD-like diurnal and nocturnal hyperactivity and anomalies in the rhythmicity of home cage activity that are reversibly rescued by MPH and modulated by voluntary nicotine consumption. DNE mice are hyperactive in the open field and display increased risk-taking behaviors that are normalized by MPH. Pharmacological characterization of nicotinic and dopaminergic systems in striatum and frontal cortex reveals altered expression and dysfunction of nicotinic acetylcholine receptors (nAChRs), hypersensitivity to nicotine-induced nAChR-mediated dopamine release, and impaired dopamine transporter (DAT) function in DNE mice. Global DNA methylation assays indicate DNA methylome deficits in striatum and frontal cortex of DNE mice. Collectively, our data demonstrate that DNE enhances nicotine preference, elicits hyperactivity and risk-taking behaviors, perturbs the rhythmicity of activity, alters nAChR expression and function, impairs DAT function, and causes DNA hypomethylation in striatum and frontal cortex of both first and second-generation adolescent offspring. These findings recapitulate multiple domains of ADHD symptomatology.
母体在怀孕期间吸烟，即发育性尼古丁暴露（DNE）的一种形式，与儿童尼古丁使用增加和神经发育障碍（如 ADHD）有关。在这里，我们描述了在怀孕前和整个繁殖期暴露于尼古丁的小鼠的 F1（第一代）和 F2（第二代）青少年后代的行为、节律计量、神经药理学和表观遗传后果。我们评估了被动口服哌醋甲酯（MPH）给药和自愿吸烟对笼内活动节律以及在开放场中的活动和冒险行为的影响。结果表明，DNE 小鼠存在多代尼古丁消费倾向，并证明了 ADHD 样的昼夜活动过度和笼内活动节律异常，这些异常可通过 MPH 逆转并通过自愿吸烟调节。DNE 小鼠在开放场中表现出过度活跃，并显示出增加的冒险行为，这些行为可通过 MPH 正常化。纹状体和额叶皮层中的烟碱型乙酰胆碱受体（nAChRs）和多巴胺转运蛋白（DAT）功能障碍，以及 DNE 小鼠中尼古丁诱导的 nAChR 介导的多巴胺释放的超敏性的药理学特征表明，DNE 小鼠中的尼古丁和多巴胺系统发生改变。在纹状体和额叶皮层中，全基因组 DNA 甲基化测定表明 DNE 小鼠的 DNA 甲基组存在缺陷。总的来说，我们的数据表明，DNE 增强了尼古丁的偏好，引起了过度活跃和冒险行为，扰乱了活动的节律性，改变了 nAChR 的表达和功能，损害了 DAT 功能，并导致纹状体和额叶皮层中的 DNA 低甲基化。这些发现概括了 ADHD 症状的多个领域。
