The Allosteric Potentiation of Nicotinic Acetylcholine Receptors by Galantamine Ameliorates the Cognitive Dysfunction in Beta Amyloid25–35 I.c.v.-Injected Mice: Involvement of Dopaminergic Systems
The Allosteric Potentiation of Nicotinic Acetylcholine Receptors by Galantamine Ameliorates the Cognitive Dysfunction in Beta Amyloid25–35 I.c.v.-Injected Mice: Involvement of Dopaminergic Systems
复制标题
DOI：
10.1038/sj.npp.1301256
复制
发表时间：
2007-06
影响因子：
7.6
通讯作者：
Dayong Wang;Y. Noda;Yuan Zhou;A. Mouri;H. Mizoguchi;A. Nitta;Weiduo Chen;T. Nabeshima
中科院分区：
文献类型：
--
作者：
Dayong Wang;Y. Noda;Yuan Zhou;A. Mouri;H. Mizoguchi;A. Nitta;Weiduo Chen;T. Nabeshima
加兰他敏（Galantamine）是一种新型的胆碱能药物，具有抑制乙酰胆碱酯酶和变构调节烟碱型乙酰胆碱受体（nAChRs）的双重作用，从而刺激儿茶酚胺类神经递质。在本研究中，我们研究了加兰他敏是否通过脑室内注射β淀粉样蛋白（Aβ）25− 35的阿尔茨海默病动物模型中nAChR的变构调节来发挥认知改善作用。加兰他敏（3 mg/kg po）显著增加了注射生理盐水和Aβ 25− 35的小鼠海马中细胞外多巴胺的释放。加兰他敏可增强尼古丁对细胞外多巴胺释放的影响，但nAChR拮抗剂美加明可拮抗尼古丁对细胞外多巴胺释放的影响。与注射生理盐水的小鼠相比，注射Aβ 25− 35的小鼠在新物体识别测试中无法区分新物体和熟悉物体，并且在恐惧条件反射任务中表现出较少的冻结反应，这表明Aβ 25− 35诱导了认知障碍。加兰他敏改善了Aβ 25− 35在新物体识别和恐惧条件反射任务中诱导的认知障碍。加兰他敏的这些改善作用可被美卡拉明、多巴胺D1受体拮抗剂SCH-23390和多巴胺D2受体拮抗剂舒必利阻断，但不能被毒蕈碱型乙酰胆碱受体拮抗剂东莨菪碱阻断。这项研究提供了第一个体内证据，加兰他敏通过nAChR的变构增强作用增强海马内的多巴胺能神经传递。加兰他敏对Aβ 25− 35诱导的认知障碍的改善作用可能至少部分通过激活多巴胺能系统介导，而多巴胺释放的增强可能是加兰他敏治疗获益的多种机制之一。
Galantamine, a drug for Alzheimer’s disease, is a novel cholinergic agent with a dual mode of action, which inhibits acetylcholinesterase and allosterically modulates nicotinic acetylcholine receptors (nAChRs), as a result stimulates catecholamine neurotransmission. In the present study, we investigated whether galantamine exerts cognitive improving effects through the allosteric modulation of nAChR in the intracerebroventricular beta amyloid (Aβ) 25− 35-injected animal model of Alzheimer’s disease. Galantamine (3 mg/kg po) significantly increased the extracellular dopamine release in the hippocampus of saline-and Aβ 25− 35-injected mice. The effects of nicotine on the extracellular dopamine release were potentiated by galantamine, but antagonized by mecamylamine, a nAChR antagonist. Aβ 25− 35-injected mice, compared with saline-injected mice, could not discriminate between new and familiar objects in the novel object recognition test and exhibited less freezing response in the fear-conditioning tasks, suggesting Aβ 25− 35 induced cognitive impairment. Galantamine improved the Aβ 25− 35-induced cognitive impairment in the novel object recognition and fear-conditioning tasks. These improving effects of galantamine were blocked by the treatment with mecamylamine, SCH-23390, a dopamine-D1 receptor antagonist, and sulpiride, a dopamine-D2 receptor antagonist, but not by scopolamine, a muscarinic acetylcholine receptor antagonist. This study provides the first in vivo evidence that galantamine augments dopaminergic neurotransmission within the hippocampus through the allosteric potentiation of nAChRs. The improving-effects of galantamine on the Aβ 25− 35-induced cognitive impairment may be mediated through the activation of, at least in part, dopaminergic systems, and the enhancement of dopamine release may be one of multiple mechanisms underlying the therapeutic benefit of galantamine.