Molecular mechanisms of drug dependency and stimulant psychosis induced by methamphetamine

甲基苯丙胺诱发药物依赖和兴奋性精神病的分子机制

基本信息

批准号：
15390080
负责人：
MIKI Naomasa
金额：
$ 9.92万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390080/
关键词：
methamphetamine gene expression Arc Arcadline N-cadherin MAP2 synaptic remodeling stimulant psychosis methamphetamine Arcadline synaptic remodeling stimulant psychosis 精神依存 Arc シナプス樹状突起

项目摘要

We hypothesizes that drug dependency and stimulant psychosis induced by methamphetamine are triggered by gene expression which causes remodeling of the synapses in the nucleus accumbens. We analyzed the functions of Arc and Arcadline which are induced by methamphetamine.1)Arcadlin : Neural activity induces structural changes of synapse in which the cell adhesion molecules participate. We found that synapses were expanded laterally in 30 minutes after depolarization. N-cadherin participated in expansion of synapse adhesion plane. Moreover, both AMPA receptor and polymerization of actin are necessary.On the other hand, Arcadlin is a cadherin family and induced by neural activity. We found that Arcadlin formed a complex with N-cadherin and was internalized, and then the number of synapses decreased. Conversely, the neurons from Arcadlin knockout mice increased the number of synapses.2)Arc : Arc is an immediate early gene induced by methamphetamine and its mRNA is carried to the dendrite to synthesize the protein. It was found that the immunoreactivity of MAP2 was markedly decreased by overexpression of Arc. When the electric shock convulsive seizure was applied to mice, immunostaining of Arc was increased in the granular layer and that of MAP was significantly decreased.From these data, Arcadline and Arc which are induced by methamphetamine associate with other proteins to change the synaptic morphology and functions, which may cause drug dependence and stimulant psychosis.

我们假设甲基苯丙胺引起的药物依赖和兴奋性精神病是由基因表达触发的，基因表达导致伏隔核中突触的重塑。我们分析了甲基苯丙胺诱导的Arc和Arcadline的功能。1)Arcadlin：神经活动引起细胞粘附分子参与的突触结构变化。我们发现去极化后 30 分钟内突触横向扩展。 N-钙粘蛋白参与突触粘附平面的扩展。此外，AMPA受体和肌动蛋白的聚合都是必需的。另一方面，Arcadlin是钙粘蛋白家族，由神经活动诱导。我们发现Arcadlin与N-cadherin形成复合物并被内化，然后突触数量减少。相反，Arcadlin敲除小鼠的神经元突触数量增加。2)Arc：Arc是甲基苯丙胺诱导的立即早期基因，其mRNA被携带到树突以合成蛋白质。结果发现，Arc 的过度表达显着降低了 MAP2 的免疫反应性。当对小鼠进行电击惊厥发作时，颗粒层中Arc的免疫染色增加，而MAP的免疫染色明显减少。从这些数据来看，甲基苯丙胺诱导的Arcadline和Arc与其他蛋白质结合，改变了突触形态，并导致突触形态发生改变。功能，可能导致药物依赖和兴奋性精神病。