Ifenprodil Attenuates Methamphetamine-Induced Behavioral Sensitization and Activation of Ras-ERK-ΔFosB Pathway in the Caudate Putamen
Ifenprodil Attenuates Methamphetamine-Induced Behavioral Sensitization and Activation of Ras-ERK-ΔFosB Pathway in the Caudate Putamen
复制标题
艾芬地尔减弱甲基苯丙胺诱导的行为敏感和尾壳核 Ras-ERK-Delta FosB 通路的激活
DOI：
10.1007/s11064-016-1976-z
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发表时间：
2016-10-01
影响因子：
4.4
通讯作者：
Li, Tao
中科院分区：
文献类型：
--
作者：
Li, Lu;Liu, Xinshe;Li, Tao
成瘾是一种使人衰弱的慢性精神疾病，由于复发率高，很难完全治愈。行为敏化被认为可能是行为改变的基础，如复发，由长期滥用精神运动兴奋剂引起的。因此，其动物模型已被广泛用于探索成瘾的病因。近年来，越来越多的证据表明n -甲基-d-天冬氨酸受体（NMDARs）在精神运动兴奋剂成瘾中起重要作用。然而，含glun2b受体及其下游信号通路在甲基苯丙胺（METH）诱导的行为致敏中的作用尚未得到研究。在这项研究中，我们使用不同剂量的GluN2B亚基选择性拮抗剂伊芬地尔（2.5、5、10 mg/kg）来研究含GluN2B的NMDARs在甲基甲氧嘧啶诱导的行为致敏中的作用。然后，我们通过western blot检测了尾状壳核（CPu）中Ras、磷酸化的细胞外信号调节激酶(pERK)/ERK和匕首FosB水平的变化。我们发现，2.5或10 mg/kg的伊芬普罗地尔显著减弱甲基苯丙胺诱导的行为致敏，而中等剂量的伊芬普罗地尔（5 mg/kg）处理的小鼠没有明显变化。进一步的western blot实验结果表明，甲基安非他明可引起大鼠CPu中Ras、pERK/ERK和FosB水平升高，而仅2.5 mg/kg剂量的伊芬普罗地尔可抑制这些变化。综上所述，2.5 mg/kg的伊芬普罗地尔可以减轻甲基苯丙胺引起的行为致敏。此外，含有glun2b的NMDARs及其在CPu中的下游Ras-ERK-a匕首FosB信号通路可能参与了meth诱导的行为致敏。
Addiction is a debilitating, chronic psychiatric disorder that is difficult to cure completely owing to the high rate of relapse. Behavioral sensitization is considered to may underlie behavioral changes, such as relapse, caused by chronic abuse of psychomotor stimulants. Thus, its animal models have been widely used to explore the etiology of addiction. Recently, increasing evidence has demonstrated that N-methyl-d-aspartate receptors (NMDARs) play an important role in addiction to psychomotor stimulants. However, the role of GluN2B-containing receptors and their downstream signaling pathway(s) in behavioral sensitization induced by methamphetamine (METH) have not been investigated yet. In this study, we used different doses of ifenprodil (2.5, 5, 10 mg/kg), a selective antagonist of the GluN2B subunit, to investigate the role of GluN2B-containing NMDARs in METH-induced behavioral sensitization. We then examined changes in the levels of Ras, phosphorylated extracellular signal-regulated kinase (pERK)/ERK, and a dagger FosB in the caudate putamen (CPu) by western blot. We found that 2.5 or 10 mg/kg ifenprodil significantly attenuated METH-induced behavioral sensitization, whereas the mice treated with a moderate dose of ifenprodil (5 mg/kg) displayed no significant changes. Further results of western blot experiments showed that repeated administration of METH caused the increases in the levels of Ras, pERK/ERK and a dagger FosB in the CPu, and these changes were inhibited by only the 2.5 mg/kg dose of ifenprodil. In conclusion, these results demonstrated that 2.5 mg/kg ifenprodil could attenuate METH-induced behavioral sensitization. Moreover, GluN2B-containing NMDARs and their downstream Ras-ERK-a dagger FosB signaling pathway in the CPu might be involved in METH-induced behavioral sensitization.