Striatal dopamine receptors become supersensitive while rats are given trifluoperazine for six months
Striatal dopamine receptors become supersensitive while rats are given trifluoperazine for six months
复制标题
当大鼠服用三氟拉嗪六个月时，纹状体多巴胺受体变得超级敏感
作者：
Angela Clow;P. Jenner;A. Theodorou;C. Marsden
在用于治疗精神分裂症等精神病的药物的所有副作用中，慢性迟发性运动障碍是最令人不安的。在数月或数年的治疗后，它们会出现，并且在大约一半的病例中，当违规药物被停用时，它们会持续存在。这种迟发性运动障碍在特征上类似于帕金森病患者左旋多巴引起的异常运动。它们可以被拮抗多巴胺(DA)1的大脑活动的药物控制。因此，它们似乎是由于大脑DA受体的过度刺激造成的，尽管它们是由在急性实验中拮抗大脑多巴胺受体Action2-5的抗神经药引起的。这一悖论已被解决，方法是表明此类药物通过与大脑DA受体结合并拮抗，最终可能实际上提高了受体的敏感性。事实上，在用吩噻嗪或丁苯酮治疗数周并停药后，动物表现出对DA激动剂的行为和生化超敏，这种超敏持续一段时间6-13。然而，当患者继续服用违禁药物时，通常会出现迟发性运动障碍，因此我们研究了临床常用的强效抗神经药(三氟拉嗪)连续6个月给药对大鼠纹状体DA受体活性的影响。每隔一段时间，动物就会被测试对DA激动剂阿朴吗啡的行为反应，并被处死，以进行DA周转和大脑部分(纹状体)DA受体活性的生化评估，该部分被认为是产生迟发性运动障碍的部位。我们在这里报告，最初的行为和生化证据，纹状体DA受体阻断三氟拉嗪在开始治疗的几周内消失，取而代之的是在给药6个月后的超敏反应，尽管继续服药。
OF all the side effects of drugs used to treat psychotic illness such as schizophrenia, chronic tardive dyskinesias are the most disturbing. They appear after months or years of therapy, and persist when the offending drug is withdrawn in about half of the cases. Such tardive dyskinesias resemble in character abnormal movements produced by levodopa in patients with Parkinson's disease. They can be controlled by drugs that antagonise the cerebral actions of dopamine (DA)1. Thus, they seem to be due to overstimulation of cerebral DA receptors, although they are caused by neuroleptic drugs which, in acute experiments, antagonise cerebral dopamine receptor action2–5. This paradox has been resolved by suggesting that such drugs, by binding to and antagonising cerebral DA receptors, may eventually actually increase receptor sensitivity. Indeed, following treatment for a few weeks with phenothiazines or butyrophenones and withdrawal of the drugs, animals exhibit behavioural and biochemical supersensitivity to DA agonists which persists for some time6–13. However, tardive dyskinesias usually appear while the patient continues to take the offending drug, so we have studied the effect on striatal DA receptor activity of continuous 6-month administration to rats of a potent neuroleptic drug in common clinical use (trifluoperazine). At intervals the animals were tested for a behavioural response to the DA agonist apomorphine, and were killed for biochemical assessment of DA turnover and DA receptor activity in that part of the brain (the corpus striatum) believed to be the site responsible for production of tardive dyskinesias. We report here that the initial behavioural and biochemical evidence for striatal DA receptor blockade by trifluoperazine disappears within a few weeks of starting therapy, to be replaced by supersensitivity after 6 months of drug administration, despite continued drug intake.