Centrally acting non-narcotic antitussives prevent hyperactivity in mice: Involvement of GIRK channels
Centrally acting non-narcotic antitussives prevent hyperactivity in mice: Involvement of GIRK channels
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DOI：
10.1016/j.pbb.2016.02.006
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发表时间：
2016-05-01
影响因子：
3.6
通讯作者：
Takahama, Kazuo
中科院分区：
文献类型：
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作者：
Soeda, Fumio;Fujieda, Yoshiko;Takahama, Kazuo
我们以前曾报道，中枢作用的非麻醉性镇咳药抑制G蛋白偶联内向整流钾（GIRK）通道激活电流，并且镇咳药对啮齿动物的各种顽固性脑疾病模型具有多种药理作用。在这项研究中，这些止咳药是否抑制药物诱导的小鼠多动症的问题进行了调查。止咳药，如氯哌斯汀和替匹定，在止咳剂量下，抑制了用6-羟基多巴胺经直肠给药的小鼠的振幅增加。此外，所有研究的镇咳药都抑制了小鼠中甲基苯丙胺诱导的多动症的增加。哌甲酯，这是用于治疗多动症，抑制6-羟基多巴胺损伤诱导的，但不是甲基苯丙胺诱导的，在小鼠多动症。转杆实验表明，药物对多动小鼠的运动协调性无明显影响。止咳药对甲基苯丙胺诱导的多动症的改善作用与其对GIRK通道电流的抑制作用之间存在显著相关性（系数因子为0.998）。此外，特硫平，GIRK通道阻滞剂，防止甲基苯丙胺诱导的小鼠多动症的增加。这些结果表明，对GIRK通道具有抑制作用的止咳药物（氯哌斯汀、替匹定和卡拉米芬）可以抑制药物诱导的小鼠多动症，这表明此类止咳药物可能对ADHD患者有潜在的治疗作用。(C)2016 Elsevier Inc. All rights reserved.
We have previously reported that centrally acting non-narcotic antitussives inhibited G protein-coupled inwardly rectifying potassium (GIRK) channel-activated currents, and that the antitussives had multiple pharmacological actions on various models of intractable brain diseases in rodents. In this study, the question of whether these antitussives inhibit drug-induced hyperactivity in mice was investigated. Antitussives, such as cloperastine and tipepidine, at cough suppressant doses, inhibited an increase in ambulation of mice neonatally treated with 6-hydroxydopamine. In addition, all antitussives studied inhibited an increase in methamphetamine-induced hyperactivity in mice. Methylphenidate, which is used for treatment of ADHD, inhibited 6-hydroxydopaminelesion-induced, but not methamphetamine-induced, hyperactivity in mice. By the rota-rod test, the drugs had little effect on motor coordination of the hyperactive mice. Significant correlation was found between the ameliorating effects of antitussives on methamphetamine-induced hyperactivity and their inhibitory actions on GIRK channel currents (coefficient factor, 0.998). Furthermore, tertiapin, a GIRK channel blocker, prevented an increase in methamphetamine-induced hyperactivity of mice. These results demonstrated that antitussive drugs (cloperastine, tipepidine and caramiphen) possessing inhibitory action on GIRK channels inhibit drug-induced hyperactivity in mice, suggesting that such antitussives may potentially be therapeutic for patients with ADHD. (C) 2016 Elsevier Inc. All rights reserved.