Abstract

Perinatal nicotine exposure (PNE) produces frontal cortical hypo-dopaminergic state and attention and working memory deficits consistent with neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD). Methylphenidate alleviates ADHD symptoms by increasing extracellular dopamine and noradrenaline. Kappa opioid receptor (KOR) antagonism may be another mechanism to achieve the same results because KOR activation inhibits frontal cortical dopamine release. We administered the selective KOR antagonist norbinaltorphimine (norBNI) (20 mg/kg; intraperitoneal) or methylphenidate (0.75 mg/kg; intraperitoneal) to PNE mouse model and examined frontal cortical monoamine release, attention, and working memory. Both compounds increased dopamine and noradrenaline release but neither influenced serotonin release. Both compounds improved object-based attention and working memory in the PNE group, with norBNI’s effects evident at 2.5 h and 5.5 h but absent at 24 h. Methylphenidate’s effects were evident at 0.5 h but not at 2.5 h. norBNI’s effects temporally coincided with frontal cortical c-Jun N-terminal kinase phosphorylation. norBNI did not alter tissue dopamine content in the nucleus accumbens, offering preliminary support for lack of reinforcement.

中文翻译：

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Kappa 阿片受体拮抗剂围产期尼古丁暴露小鼠模型中额皮质单胺释放、注意力和工作记忆。

 抽象的

围产期尼古丁暴露（PNE）会导致额叶皮质低多巴胺能状态以及注意力和工作记忆缺陷，这与注意力缺陷多动障碍（ADHD）等神经发育障碍一致。哌醋甲酯通过增加细胞外多巴胺和去甲肾上腺素来缓解多动症症状。 Kappa 阿片受体 (KOR) 拮抗可能是实现相同结果的另一种机制，因为 KOR 激活会抑制额叶皮质多巴胺的释放。我们对 PNE 小鼠模型施用选择性 KOR 拮抗剂去甲托菲明 (norBNI)（20 mg/kg；腹膜内注射）或哌醋甲酯（0.75 mg/kg；腹膜内注射），并检查额皮质单胺释放、注意力和工作记忆。这两种化合物都会增加多巴胺和去甲肾上腺素的释放，但都不影响血清素的释放。两种化合物均改善了 PNE 组的基​​于对象的注意力和工作记忆，norBNI 的效果在 2.5 小时和 5.5 小时时明显，但在 24 小时时消失。哌醋甲酯的作用在 0.5 小时时明显，但在 2.5 小时时不明显。 norBNI 的作用在时间上与额叶皮质 c-Jun N 末端激酶磷酸化同时发生。 NorBNI 没有改变伏隔核中的组织多巴胺含量，为缺乏强化提供了初步支持。