Division of Clinical Sciences and Neuropsychopharmacology, Meijo University, Graduate School of Pharmaceutical Science, Nagoya, Japan.
Int J Neuropsychopharmacol. 2010 Nov;13(10):1343-54. doi: 10.1017/S1461145710000222. Epub 2010 Mar 11.
Galantamine, a drug used to treat Alzheimer's disease, inhibits acetylcholinesterase (AChE) and allosterically modulates nicotinic acetylcholine receptors (nAChRs) resulting in stimulation of catecholamine neurotransmission. In this study, we investigated whether galantamine exerts cognitive-improving effects through the allosteric modulation of nAChRs in an animal model of methamphetamine (Meth) psychosis. The mice treated with Meth (1 mg/kg.d) for 7 d showed memory impairment in a novel object recognition test. Galantamine (3 mg/kg) ameliorated the memory impairment, and it increased the extracellular dopamine release in the prefrontal cortex (PFC) of Meth-treated mice. Donepezil, an AChE inhibitor (1 mg/kg) increased the extracellular ACh release in the PFC, whereas it had no effect on the memory impairment in Meth-treated mice. The nAChR antagonist, mecamylamine, and dopamine D1 receptor antagonist, SCH 23390, blocked the ameliorating effect of galantamine on Meth-induced memory impairment, whereas the muscarinic AChR antagonist, scopolamine, had no effect. The effects of galantamine on extracellular dopamine release were also antagonized by mecamylamine. Galantamine attenuated the defect of the novelty-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2). The ameliorating effect of galantamine on recognition memory in Meth-treated mice was negated by microinjection of an ERK inhibitor, PD98059, into the PFC. These results suggest that the ameliorating effect of galantamine on Meth-induced memory impairment is associated with indirect activation of dopamine D1 receptor-ERK1/2 following augmentation with dopaminergic neurotransmission in the PFC through the allosteric activation of nAChRs. Galantamine could be a useful therapeutic agent for treating cognitive deficits in schizophrenia/Meth psychosis, as well as Alzheimer's disease.
加兰他敏是一种用于治疗阿尔茨海默病的药物，它抑制乙酰胆碱酯酶（AChE）并变构调节烟碱型乙酰胆碱受体（nAChRs），从而刺激儿茶酚胺神经递质的传递。在这项研究中，我们研究了加兰他敏是否通过变构调节 nAChRs 来改善 methamphetamine（Meth）精神病动物模型中的认知功能。用 Meth（1mg/kg.d）处理 7 天的小鼠在新物体识别测试中表现出记忆障碍。加兰他敏（3mg/kg）改善了记忆障碍，并增加了 Meth 处理小鼠前额叶皮质（PFC）的细胞外多巴胺释放。乙酰胆碱酯酶抑制剂多奈哌齐（1mg/kg）增加了 PFC 中的细胞外 ACh 释放，但对 Meth 处理的小鼠的记忆障碍没有影响。nAChR 拮抗剂美金刚胺和多巴胺 D1 受体拮抗剂 SCH 23390 阻断了加兰他敏对 Meth 诱导的记忆障碍的改善作用，而毒蕈碱型乙酰胆碱受体拮抗剂东莨菪碱则没有影响。加兰他敏对细胞外多巴胺释放的作用也被美金刚胺拮抗。加兰他敏减弱了新奇诱导的细胞外信号调节激酶 1/2（ERK1/2）激活的缺陷。将 ERK 抑制剂 PD98059 微注射到 PFC 中，会否定加兰他敏对 Meth 处理的小鼠识别记忆的改善作用。这些结果表明，加兰他敏对 Meth 诱导的记忆障碍的改善作用与通过变构激活 nAChRs 增强 PFC 中的多巴胺能神经传递后间接激活多巴胺 D1 受体-ERK1/2 有关。加兰他敏可能是治疗精神分裂症/Meth 精神病和阿尔茨海默病认知缺陷的有效治疗药物。
