Mechanism of the histamine H3 receptor-mediated increase in exploratory locomotor activity and anxiety-like behaviours in mice
Mechanism of the histamine H3 receptor-mediated increase in exploratory locomotor activity and anxiety-like behaviours in mice
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DOI：
10.1016/j.neuropharm.2014.02.003
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发表时间：
2014-06-01
影响因子：
4.7
通讯作者：
Yanai, Kazuhiko
中科院分区：
文献类型：
--
作者：
Mohsen, Attayeb;Yoshikawa, Takeo;Yanai, Kazuhiko
组胺能神经元被组胺H-3受体(H3R)拮抗剂激活，增加大脑中的组胺和其他神经递质。H3R拮抗剂硫代巴比妥钠的原型增加了运动活性和焦虑样行为；然而，这些效应背后的机制尚未完全阐明。本研究旨在探讨H3R受体拮抗剂JNJ-10181457对H3R介导的行为改变的作用机制。首先，我们研究了JNJ对小鼠脑内单胺类物质及其代谢物浓度的影响。JNJ只增加N-J-甲基组胺，N-J-甲基组胺是脑组胺的代谢物，用作组胺释放的指标，这表明JNJ主要刺激组胺的释放，而不是其他单胺的释放。接下来，我们通过开场测试和提升的零迷宫测试来研究JNJ诱导行为变化的机制。组胺合成抑制剂α-氟甲基组氨酸可抑制JNJ引起的运动活动增加，支持H3R通过组胺神经传递发挥作用。在H1R基因敲除小鼠中保留了JNJ诱导的野生型小鼠的运动活动增加，而在组胺H-2受体(H2 R)基因敲除小鼠中则没有。HIR拮抗剂苯海拉明部分减少了JNJ诱导的焦虑样行为，而h2R拮抗剂唑兰替丁则主要减轻了JNJ诱导的焦虑样行为。这些结果表明，阻断H3R可诱导组胺释放，激活H_2R，并引起探索性运动活动和焦虑样行为。(C)2014爱思唯尔有限公司。保留所有权利。
Histaminergic neurons are activated by histamine H-3 receptor (H3R) antagonists, increasing histamine and other neurotransmitters in the brain. The prototype H3R antagonist thioperamide increases locomotor activity and anxiety-like behaviours; however, the mechanisms underlying these effects have not been fully elucidated. This study aimed to determine the mechanism underlying H3R-mediated behavioural changes using a specific H3R antagonist, JNJ-10181457 (JNJ).First, we examined the effect of JNJ injection to mice on the concentrations of brain monoamines and their metabolites. JNJ exclusively increased N-J-methylhistamine, the metabolite of brain histamine used as an indicator of histamine release, suggesting that JNJ dominantly stimulates the release of histamine release but not of other monoamines.Next, we examined the mechanism underlying JNJ-induced behavioural changes using open-field tests and elevated zero maze tests. JNJ-induced increase in locomotor activity was inhibited by a-fluoromethyl histidine, an inhibitor of histamine synthesis, supporting that H3R exerted its effect through histamine neurotransmission. The JNJ-induced increase in locomotor activity in wild-type mice was preserved in H1R gene knockout mice but not in histamine H-2 receptor (H2R) gene knockout mice. JNJ-induced anxiety-like behaviours were partially reduced by diphenhydramine, an HiR antagonist, and dominantly by zolantidine, an H2R antagonist. These results suggest that H3R blockade induces histamine release, activates H2R and elicits exploratory locomotor activity and anxiety-like behaviours. (c) 2014 Elsevier Ltd. All rights reserved.