Rivastigmine improves isolation rearing-induced prepulse inhibition deficits via muscarinic acetylcholine receptors in mice
Rivastigmine improves isolation rearing-induced prepulse inhibition deficits via muscarinic acetylcholine receptors in mice
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DOI：
10.1007/s00213-015-4123-7
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发表时间：
2016-02
影响因子：
3.4
通讯作者：
Kosuke Higashino;Y. Ago;Takahiro Umeki;Shigeru Hasebe;Y. Onaka;H. Hashimoto;K. Takuma;T. Matsuda
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文献类型：
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作者：
Kosuke Higashino;Y. Ago;Takahiro Umeki;Shigeru Hasebe;Y. Onaka;H. Hashimoto;K. Takuma;T. Matsuda
乙酰胆碱酯酶抑制剂多奈哌齐、加兰他敏和卡巴拉汀用于治疗阿尔茨海默病。我们以前证明，多奈哌齐和加兰他敏差异影响隔离饲养诱导的前脉冲抑制（PPI）赤字，这可能是由于脑毒蕈碱乙酰胆碱（MACH）受体功能的差异影响在mice.ObjectivesWe研究rivastigmine对隔离饲养诱导的PPI赤字，脑ACh水平，和MACH受体功能在mice.MethodsAcoustic惊吓反应进行了测量在惊吓室。微透析进行，和多巴胺和乙酰胆碱在前额叶皮质的水平进行了测量。ResultsRivastigmine（0.3 mg/kg）改善PPI赤字，这种改善是拮抗的乙酰胆碱受体拮抗剂telenzepine，但不是由烟碱乙酰胆碱受体拮抗剂美加明。卡巴拉汀使细胞外ACh水平增加约2-3倍，低于加兰他敏产生的增加。卡巴拉汀增强了mACh受体激动剂N-去甲基氯氮平对前额叶多巴胺释放（mACh受体功能的标志物）的作用，这种增加被替仑西平阻断。相反，加兰他敏不影响N-去甲基氯氮平诱导的多巴胺释放。此外，rivastigmine不影响皮质多巴胺释放诱导的阿糖胞苷1A受体激动剂osemozotan，这表明rivastigmine的效果具有特异性的mACh receptor. ConclusionsTogether与我们以前的发现，显着增加乙酰胆碱水平所需的PPI赤字改善加兰他敏，我们目前的结果表明，rivastigmine通过增加ACh水平和同时增强mACh受体功能来改善隔离饲养诱导的PPI缺陷。
RationaleThe acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine are used for the treatment of Alzheimer’s disease. We previously demonstrated that donepezil and galantamine differentially affect isolation rearing-induced prepulse inhibition (PPI) deficits and that this might be due to differential effects on brain muscarinic acetylcholine (mACh) receptor function in mice.ObjectivesWe examined the effects of rivastigmine on isolation rearing-induced PPI deficits, brain ACh levels, and mACh receptor function in mice.MethodsAcoustic startle responses were measured in a startle chamber. Microdialysis was performed, and the levels of dopamine and ACh in the prefrontal cortex were measured.ResultsRivastigmine (0.3 mg/kg) improved PPI deficits, and this improvement was antagonized by the mACh receptor antagonist telenzepine but not by the nicotinic ACh receptor antagonist mecamylamine. Rivastigmine increased extracellular ACh levels by approximately 2–3-fold, less than the increase produced by galantamine. Rivastigmine enhanced the effect of the mACh receptor agonistN-desmethylclozapine on prefrontal dopamine release, a marker of mACh receptor function, and this increase was blocked by telenzepine. In contrast, galantamine did not affectN-desmethylclozapine-induced dopamine release. Furthermore, rivastigmine did not affect cortical dopamine release induced by the serotonin1Areceptor agonist osemozotan, suggesting that the effect of rivastigmine has specificity for mACh receptors.ConclusionsTaken together with our previous finding that marked increases in ACh levels are required for the PPI deficit improvement induced by galantamine, our present results suggest that rivastigmine improves isolation rearing-induced PPI deficits by increasing ACh levels and by concomitantly enhancing mACh receptor function.