Molecular pathophysiology of dopamine receptors in dyskinesia

在运动障碍动物模型中，在改善运动障碍症状前后进行了分子、化学和药理学研究。结果表明：(1)在亚氨基二丙腈(IDPN)诱导的大鼠运动障碍模型中，多巴胺转换率、多巴胺D_1受体(R)、D_2-R、D_1-R和D_2-R信使核糖核酸(D2-R)、D_(1-R)、D_(1-R)、D_(2-R)m RNA减少，时序给药使这些生化变化恢复正常。免疫抑制剂环孢菌素A(CsA)在行为学和生化方面加速了IDPN诱导的运动障碍。(2)在凝胶迁移率改变分析中，CsA提高了cAMP反应元件(CRE)结合活性。(3)从IDPN处理大鼠脑内神经肽水平的结果看，基底节、后脑和大脑皮质中的神经肽可能在运动障碍症状的表现中起重要作用。(4)纹状体c-fos mRNA的表达受M胆碱能受体机制的调控。6-OHDA和H_2O_2显著降低AP-1和CREB的DNA结合活性，而在培养的神经胶质细胞中，6-OHDA和H_2O_2使AP-1结合活性增加。体内研究表明，6-OHDA脑室注射后1周，纹状体内AP-1的DNA结合活性持续增加。免疫抑制剂FK506纠正了AP-1活性的升高，使其达到对照水平。因此，免疫反应可能通过调节基因转录因子参与运动障碍的发病和病理生理过程。

In the animal model of dyskinesia, molecular, chemical and pharmacological studies were conducted before and after modification of dyskinetic symptoms. Results were :(1) In the iminodipropionitrile (IDPN) -induced dyskinesia model, dopamine turnover, dopamine D1-receptor (R), D2-R,D1-R mRNA and D2-R mRNA were reduced.Chronic administration of ceruletide normalized these biochemical changes. Immunosuppressant cyclosporine A (CsA) accelerated IDPN-induced dyskinesia in behavioraly and biochemicaly.(2) In electrophoretic mobility shift assay, CsA increased cAMP response element (CRE) binding activity in the various brain regions compared with that in the IDPN treatment alone.(3) From the results of neuropeptide levels of IDPN-treated rat brain, neuropeptides in the basal ganglia, hindbrain and cerebral cortex may play important roles in the manifestation of dyskinetic symptoms.(4) Striatal c-fos mRNA expression was under the control of muscarinic cholinergic receptor mechanis.(5) In vitro cultured neuronal cells, both DNA-binding activities of AP-1 and CREB markedly decreased with 6-OHDA and H_2O_2.While in the cultured glial cells, the AP-1 binding activity was increased with 6-OHDA and H_2O_2. In vivo study, persistent increase of DNA-binding activity of AP-1 was observed in the striatum of 6-OHDA icv-injected mice even 1 week after injection.Administration of immunosuppressant FK506 corrected this increased AP-1 activity to the control levels.Thus, immune response might be involved in pathogenesis and pathophysiology of dyskinesia through modulation of transcription factors of genes.