Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan; Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan.
Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
Biochem Pharmacol. 2020 Oct;180:114139. doi: 10.1016/j.bcp.2020.114139. Epub 2020 Jul 8.
Prenatal nicotine exposure (PNE) causes behavioral abnormalities in offspring, such as an enhancement of impulsivity and decrease in attention at adolescence. Here we examined the effects of galantamine (GAL) on the behavioral and electrophysiological changes induced by PNE in mice. Pregnant C57BL/6J mice were exposed to nicotine (0.2 mg/mL) dissolved in sweetened (2% saccharin) drinking water during gestational day 14 and perinatal day 0 (P0). At the ages of postnatal days 42-49 (P42-P49), female offspring displayed impulsivity in the cliff avoidance test and impairment of visual attention in the object-based attention test. Decrease of long-term potentiation (LTP) and extracellular glutamate levels were observed in the prefrontal cortex of PNE mice. Systemic treatment with GAL (1 mg/kg, s.c.), an allosteric potentiating ligand for the nicotinic acetylcholine receptor (nAChR) and a weak cholinesterase inhibitor, attenuated the enhancement of impulsivity and impairment of attention induced by PNE in mice. Further, GAL reversed the impairment of LTP induced by PNE in the prefrontal cortex of mice, although it failed to attenuate the decrease of extracellular glutamate levels. The effects of GAL were blocked by an α 7 nAChR antagonist, methyllycaconitine (1 mg/kg, i.p.). These results suggest that PNE during cortex development affects nicotinic cholinergic-dependent plasticity and formation of impulsivity and attention. Furthermore, GAL could be a useful drug for cognitive impairments-related to attention deficit hyperactivity disorder.
产前尼古丁暴露（PNE）会导致后代行为异常，例如青春期冲动性增强和注意力下降。在这里，我们研究了加兰他敏（GAL）对 PNE 诱导的小鼠行为和电生理变化的影响。在妊娠第 14 天和围产期第 0 天（P0），将怀孕的 C57BL/6J 小鼠暴露于溶解在加糖（2%糖精）饮水中的尼古丁（0.2mg/mL）中。在出生后第 42-49 天（P42-P49），雌性后代在悬崖回避测试中表现出冲动性，在基于物体的注意力测试中表现出视觉注意力障碍。在 PNE 小鼠的前额叶皮层中观察到长时程增强（LTP）和细胞外谷氨酸水平下降。系统给予 GAL（1mg/kg，皮下注射），一种烟碱型乙酰胆碱受体（nAChR）的变构增强配体和一种弱胆碱酯酶抑制剂，可减轻 PNE 诱导的小鼠冲动性增强和注意力障碍。此外，GAL 逆转了 PNE 诱导的小鼠前额叶皮层 LTP 的损伤，尽管它未能减轻细胞外谷氨酸水平的下降。GAL 的作用被 α7 nAChR 拮抗剂甲基马桑宁（1mg/kg，腹腔注射）阻断。这些结果表明，皮层发育过程中的 PNE 会影响烟碱型胆碱能依赖性可塑性以及冲动性和注意力的形成。此外，GAL 可能是一种用于治疗与注意力缺陷多动障碍相关认知障碍的有用药物。
