Alkam Tursun, Mamiya Takayoshi, Kimura Nami, Yoshida Aya, Kihara Daisuke, Tsunoda Yuki, Aoyama Yuki, Hiramatsu Masayuki, Kim Hyoung-Chun, Nabeshima Toshitaka
Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, USA.
Psychopharmacology (Berl). 2017 Jun;234(12):1853-1869. doi: 10.1007/s00213-017-4591-z. Epub 2017 Mar 23.
Increased risk of attention-deficit/hyperactivity disorder (AD/HD) is partly associated with the early developmental exposure to nicotine in tobacco smoke. Emerging reports link tobacco smoke exposure or prenatal nicotine exposure (PNE) with AD/HD-like behaviors in rodent models. We have previously reported that PNE induces cognitive behavioral deficits in offspring and decreases the contents of dopamine (DA) and its turnover in the prefrontal cortex (PFC) of offspring It is well known that the dysfunction of DAergic system in the brain is one of the core factors in the pathophysiology of AD/HD. Therefore, we examined whether the effects of PNE on the DAergic system underlie the AD/HD-related behavioral changes in mouse offspring. PNE reduced the release of DA in the medial PFC (mPFC) in mouse offspring. PNE reduced the number of tyrosine hydroxylase (TH)-positive varicosities in the mPFC and in the core as well as the shell of nucleus accumbens, but not in the striatum. PNE also induced behavioral deficits in cliff avoidance, object-based attention, and sensorimotor gating in offspring. These behavioral deficits were attenuated by acute treatment with atomoxetine (3 mg/kg, s.c.) or partially attenuated by acute treatment with MPH (1 mg/kg, s.c.). Taken together, our findings support the notion that PNE induces neurobehavioral abnormalities in mouse offspring by disrupting the DAergic system and improve our understanding about the incidence of AD/HD in children whose mothers were exposed to nicotine during their pregnancy.
注意缺陷多动障碍（AD/HD）风险增加部分与早期发育过程中接触烟草烟雾中的尼古丁有关。新出现的报告将烟草烟雾暴露或产前尼古丁暴露（PNE）与啮齿动物模型中的AD/HD样行为联系起来。我们之前报道过，PNE会导致后代出现认知行为缺陷，并降低后代前额叶皮质（PFC）中多巴胺（DA）的含量及其周转率。众所周知，大脑中多巴胺能系统功能障碍是AD/HD病理生理学的核心因素之一。因此，我们研究了PNE对多巴胺能系统的影响是否是小鼠后代AD/HD相关行为变化的基础。PNE降低了小鼠后代内侧前额叶皮质（mPFC）中DA的释放。PNE减少了mPFC、伏隔核核心及壳区中酪氨酸羟化酶（TH）阳性曲张体的数量，但纹状体中没有减少。PNE还导致后代在悬崖回避、基于物体的注意力和感觉运动门控方面出现行为缺陷。这些行为缺陷通过急性给予阿托莫西汀（3mg/kg，皮下注射）得以减轻，或通过急性给予哌甲酯（1mg/kg，皮下注射）部分减轻。综上所述，我们的研究结果支持以下观点，即PNE通过破坏多巴胺能系统在小鼠后代中诱导神经行为异常，并增进了我们对母亲在孕期接触尼古丁的儿童中AD/HD发病率的理解。
