Memantine ameliorates the impairment of social behaviors induced by a single social defeat stress as juveniles
Memantine ameliorates the impairment of social behaviors induced by a single social defeat stress as juveniles
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DOI：
10.1016/j.neuropharm.2022.109208
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发表时间：
2022-08-11
影响因子：
4.7
通讯作者：
Noda，Yukihiro
中科院分区：
文献类型：
--
作者：
Yoshida，Mikio;Hasegawa，Sho;Noda，Yukihiro
临床上，青少年比成年人对压力更敏感，青少年暴露于压力会产生精神症状，并导致治疗抵抗。然而，抗抑郁药对青少年精神疾病的疗效尚不清楚。在本研究中，我们调查是否表达或发展受损的社会行为被美金刚，一种非竞争性NMDA受体拮抗剂衰减。此外，我们还阐明了通过NMDA受体进行细胞内信号传导的分子机制以及美金刚对社交行为受损小鼠的改善作用。在社交互动测试前，而不是在暴露于社交失败压力前，急性施用美金刚胺，减弱了社交行为障碍。一个单一的社会失败的压力增加了NMDA受体亚基GluN 2A和细胞外信号相关激酶1/2（ERK 1/2）的磷酸化。美金刚可抑制社交行为引起的磷酸化GluN 2A和ERK 1/2的增加。在GluN 2A缺陷和药理学阻断小鼠中，通过调节ERK 1/2磷酸化，在社会互动测试中未观察到社会行为障碍。这些发现表明，美金刚通过调节NMDA受体和随后的ERK 1/2信号转导激活来改善青少年暴露于单一社会失败压力的小鼠的社会行为障碍。美金刚胺可能构成一种新的治疗药物与不良青少年经历的青少年压力相关的精神疾病。
Clinically, juveniles are more sensitive to stress than adults, and exposure to stress as juveniles prolongs psychiatric symptoms and causes treatment resistance. However, the efficacy of antidepressants for juveniles with psychiatric disorders is unknown. In the present study, we investigated whether the expression or development of impaired social behavior was attenuated by memantine, a non-competitive NMDA receptor antagonist. In addition, we clarified the molecular mechanisms related to intracellular signal transduction through NMDA receptors and the ameliorating effect of memantine in mice with impaired social behavior. Acute administration of memantine before the social interaction test, but not before exposure to social defeat stress, attenuated social behavioral impairment. A single social defeat stress increased the phosphorylation of NMDA receptor subunit GluN2A and extracellular-signal-related kinase 1/2 (ERK1/2). Memantine inhibited the increase of phosphorylated GluN2A and ERK1/2 resulting from social interaction behavior. In both GluN2A deficient and pharmacological blockaded mice, social behavioral impairment was not observed in the social interaction test through regulation of ERK1/2 phosphorylation. These findings suggest that memantine ameliorates social behavioral impairment in mice exposed to a single social defeat stress as juveniles by regulating the NMDA receptor and subsequent ERK1/2 signaling activation. Memantine may constitute a novel therapeutic drug for stress-related psychiatric disorders in juveniles with adverse juvenile experiences.