Mizoguchi Hiroyuki, Takuma Kazuhiro, Fukakusa Ayumi, Ito Yukio, Nakatani Akiko, Ibi Daisuke, Kim Hyoung-Chun, Yamada Kiyofumi
Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science & Technology, Kanazawa University, Kanazawa 920-1192, Japan.
Psychopharmacology (Berl). 2008 Feb;196(2):233-41. doi: 10.1007/s00213-007-0955-0. Epub 2007 Oct 2.
Cognitive deficits are a core feature of patients with schizophrenia and methamphetamine (METH) psychosis. We have recently found that repeated METH treatment (1 mg/kg, s.c.) in mice, which induces behavioral sensitization, impairs long-term recognition memory in a novel object recognition test (NORT) and that the impairment is ameliorated by clozapine, but not haloperidol. Recent studies indicate that minocycline, a second-generation tetracycline, has potent neuroprotective effects in various animal models of neurological diseases.
In the present study, we investigated the effect of minocycline on learning and memory in the NORT and behavioral sensitization in mice that had been administered METH for 7 days.
When minocycline (20-40 mg/kg) was administered intraperitoneally once a day for seven consecutive days to mice that had previously been treated with METH for 7 days, it ameliorated the METH-induced impairment of recognition memory in a dose-dependent manner, although the same treatment with minocycline had no effect on behavioral sensitization to METH. The administration of minocycline, together with METH, inhibited the development of METH-induced behavioral sensitization. The improvement in memory caused by minocycline was associated with an amelioration of the novelty-induced activation of extracellular signal-regulated kinase 1/2 in the prefrontal cortex of METH-treated mice.
These results suggest that minocycline is useful for the treatment of cognitive deficits in patients with METH psychosis or schizophrenia.
认知缺陷是精神分裂症和甲基苯丙胺（METH）所致精神病患者的核心特征。我们最近发现，在小鼠中重复给予METH（1 mg/kg，皮下注射）可诱导行为敏化，在新颖物体识别测试（NORT）中损害长期识别记忆，且氯氮平可改善这种损害，而氟哌啶醇则不能。最近的研究表明，第二代四环素米诺环素在各种神经疾病动物模型中具有强大的神经保护作用。
在本研究中，我们研究了米诺环素对连续7天给予METH的小鼠在NORT中的学习和记忆以及行为敏化的影响。
对先前连续7天接受METH治疗的小鼠连续7天每天腹腔注射一次米诺环素（20 - 40 mg/kg），它以剂量依赖的方式改善了METH诱导的识别记忆损害，尽管相同剂量的米诺环素对METH诱导的行为敏化没有影响。米诺环素与METH一起给药可抑制METH诱导的行为敏化的发展。米诺环素引起的记忆改善与METH处理小鼠前额叶皮质中由新奇诱导的细胞外信号调节激酶1/2激活的改善有关。
这些结果表明，米诺环素可用于治疗METH所致精神病或精神分裂症患者的认知缺陷。
