Molecular mechanisms of drug dependency and stimulant psychosis induced by methamphetamine

我们推测甲基苯丙胺引起的药物依赖和兴奋剂性精神病是由基因表达引起伏隔核突触重塑引发的。分析了甲基苯丙胺诱导的Arc和Arcadline的功能。1)Arcadlin：神经活动诱导突触结构改变，细胞粘附分子参与其中。我们发现去极化后30分钟突触向外侧扩张。n -钙粘蛋白参与突触粘附面扩张。此外，AMPA受体和肌动蛋白的聚合都是必需的。另一方面，Arcadlin是一个钙粘蛋白家族，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，来自Arcadlin基因敲除小鼠的神经元增加了突触的数量。2)Arc: Arc是甲基苯丙胺诱导的即时早期基因，其mRNA被携带到树突合成蛋白质。结果表明，过表达Arc可显著降低MAP2的免疫反应性。小鼠经电击惊厥发作后，颗粒层Arc免疫染色增加，MAP免疫染色明显降低。从这些数据来看，甲基苯丙胺诱导的Arcadline和Arc与其他蛋白结合改变突触形态和功能，可能导致药物依赖和兴奋剂性精神病。

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.