The histamine H3-receptor inverse agonist Pitolisant improves fear memory in mice
The histamine H3-receptor inverse agonist Pitolisant improves fear memory in mice
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DOI：
10.1016/j.bbr.2012.12.063
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发表时间：
2013-04-15
影响因子：
2.7
通讯作者：
Tirelli, Ezio
中科院分区：
文献类型：
--
作者：
Brabant, Christian;Charlier, Yana;Tirelli, Ezio
大量研究表明，脑组织胺在学习和记忆中起着至关重要的作用，组胺H-3受体反向激动剂(H3R反向激动剂)已被提出用于治疗认知障碍。Pitolisant(BF2.649，1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine，盐酸盐)是第一种经过人体试验的H3R反向激动剂，耐受性良好。本研究考察了匹托利松(0.625-20 mg/kg，i.p.)改善雌性C57BL/6J小鼠在恐惧条件反射任务中的巩固和再巩固过程。我们还检测了匹托利辛是否能逆转非竞争性N-甲基-D-天冬氨酸(NMDA)拮抗剂地佐西平(MK-801)所致的记忆障碍。我们的结果表明，训练后全身注射匹托利辛有助于巩固情景恐惧记忆，并逆转由ip诱导的健忘。注射地佐西平0.12 mg/kg。此外，我们在重新激活(重新暴露在48小时前进行训练的环境中)后测试的匹托利松剂量都没有影响再巩固，而地佐西平则破坏了再巩固。但匹托利松能逆转0.12 mg/kg地佐西平引起的再巩固不足。目前的结果首次证明了匹托利松在改善恐惧条件任务中的巩固过程方面是有效的，并为其治疗认知障碍的潜力提供了进一步的证据。(C)2013爱思唯尔B.V.保留所有权利。
Numerous studies have demonstrated that brain histamine plays a crucial role in learning and memory and histamine H-3 receptor inverse agonists (H3R inverse agonists) have been proposed to treat cognitive disorders. Pitolisant (BF2.649, 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, hydrochloride) was the first H3R inverse agonist that has been tested in human trials and is well tolerated. The present study investigated whether Pitolisant (0.625-20 mg/kg, i.p.) improves consolidation and reconsolidation processes in the fear conditioning task in female C57BL/6J mice. We also tested whether Pitolisant reverses memory deficits induced by the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801). Our results indicate that post-training systemic injections of Pitolisant facilitated consolidation of contextual fear memory and reversed amnesia induced by an i.p. injection of 0.12 mg/kg dizocilpine. In addition, none of the doses of Pitolisant we have tested after reactivation (reexposure to the context in which training took place 48 h earlier) affected reconsolidation, whereas dizocilpine disrupted it. However, Pitolisant was able to reverse the deficit in reconsolidation induced by 0.12 mg/kg dizocilpine. The present results are the first demonstration that Pitolisant is effective in improving consolidation processes in the fear condition task and add further evidence to its potential for treating cognitive disorders. (C) 2013 Elsevier B.V. All rights reserved.