Van Kampen J M, Stoessl A J
Neurodegenerative Disorders Centre, Faculty of Medicine, University of British Columbia, 2221 Wesbrook Mall, B.C., V6T 2B5, Vancouver, Canada.
Neuroscience. 2000;101(3):629-35. doi: 10.1016/s0306-4522(00)00412-7.
Tardive dyskinesia develops as a common complication of long-term neuroleptic use. The emergence of such dyskinesias may reflect a shift in the balance of dopamine D(1) and D(2) receptor-mediated activity, with a relative increase in activity in the D(1) receptor-regulated direct striatonigral pathway. In rats, chronic treatment with the antipsychotic fluphenazine triggers a syndrome of vacuous chewing movements, which are attenuated by dopamine D(1) receptor antagonists. A similar syndrome can be seen in drug-naive animals following acute administration of selective dopamine D(1) receptor agonists. However, not all dopamine D(1) receptor agonists elicit these mouth movements. Thus, some investigators have suggested the existence of novel subtypes of the dopamine D(1) receptor. In these studies, we sought to clarify the role of the dopamine D(1A) receptor in vacuous chewing movements induced both by the selective dopamine D(1) receptor agonist SKF 38393, as well as by chronic neuroleptic administration, using in vivo oligonucleotide antisense to dopamine D(1A) receptor messenger RNA. Intrastriatal antisense treatment significantly and selectively attenuated striatal dopamine D(1) receptor binding, accompanied by reductions in SKF 38393- and chronic fluphenazine-induced vacuous chewing movements. These findings suggest that the dopamine D(1A) receptor plays an important role in the expression of vacuous chewing movements in a rodent model of tardive dyskinesia and may contribute to the pathogenesis of the human disorder. This may have important implications for the treatment of tardive dyskinesia in humans.
迟发性运动障碍是长期使用抗精神病药物的常见并发症。此类运动障碍的出现可能反映了多巴胺D(1)和D(2)受体介导的活性平衡发生了变化，其中D(1)受体调节的直接纹状体黑质通路的活性相对增加。在大鼠中，用抗精神病药物氟奋乃静进行慢性治疗会引发一种无意义咀嚼运动综合征，多巴胺D(1)受体拮抗剂可减轻这种症状。在未接触过药物的动物中，急性给予选择性多巴胺D(1)受体激动剂后也可观察到类似的综合征。然而，并非所有多巴胺D(1)受体激动剂都会引发这些口腔运动。因此，一些研究人员提出存在多巴胺D(1)受体的新型亚型。在这些研究中，我们试图通过对多巴胺D(1A)受体信使核糖核酸使用体内寡核苷酸反义技术，来阐明多巴胺D(1A)受体在由选择性多巴胺D(1)受体激动剂SKF 38393以及慢性抗精神病药物给药所诱导的无意义咀嚼运动中的作用。纹状体内反义治疗显著且选择性地减弱了纹状体多巴胺D(1)受体结合，同时减少了SKF 38393和慢性氟奋乃静诱导的无意义咀嚼运动。这些发现表明，多巴胺D(1A)受体在迟发性运动障碍啮齿动物模型的无意义咀嚼运动表达中起重要作用，可能与人类疾病的发病机制有关。这可能对人类迟发性运动障碍的治疗具有重要意义。
