DRUG HOLIDAYS IN CHRONIC NEUROLEPTICS: AN ANIMAL MODEL

迟发性运动障碍(TD)是一种严重的内源性疾病， 慢性精神分裂症患者的逐渐发展 神经镇静剂。这个实验室开发出了一种非常独特的 基于计算机化的迟发性运动障碍动物模型 测量大鼠口腔运动(OMS)的系统 与报告一起直接存储到计算机内存中 人类观察者。使用这一高度新颖的技术所获得的结果 和严谨的方法与所获得的非常不同 使用简单的观察技术，并建议最佳模型 大鼠的TD是嘴唇的微小颤动 大鼠在服用了几个月的慢性抗精神病药物后才开始出现症状。 这在很大程度上是肉眼看不到的。 我们现在提议进一步研究这种有希望的动物 通过进一步澄清迟发性运动障碍的模型 计算机分析和放大记录程序，什么是 微小的口腔摆动实际上代表着。其他研究将 了解是否采用不同的抗精神病药物给药方案 改变慢性阻塞性肺疾病持续性副作用的发展 抗精神病药物，包括波动或非常稳定的水平 更容易引发这种疾病。我们也 建议比较不同类别的 抗精神病药物(包括几种新的、非典型的抗精神病药物)诱导 这种紊乱，以及同时给药是否 选定的多巴胺兴奋剂(D1v.D2激动剂)促进或 阻碍了证候的发展。其他研究将 进一步研究口腔运动的药理作用 作用于多巴胺、乙酰胆碱或GABA系统的药物 在大脑中，然后比较这些化合物对 慢性动物的TD样空泡膜。详细的地区， 受体结合的放射自显影研究将在 慢性抗精神病药动物在完成这些 实验使不同程度的症状可以 与大脑生化的局部改变有关。 这些实验解决了一个重要的研究问题，涉及到 广泛存在的医源性疾病。实验问题 在本提案中解决的问题可能只在 在不久的将来，使用像这里建议的那样的动物模型。

Tardive dyskinesia (TD) is a severe latrogenic disorder which develops gradually in schizophrenics treated with chronic neuroleptics. This laboratory has developed a highly unique animal model of tardive dyskinesia based upon a computerized system in which measures of oral movements (OMs) in rats are directly placed into computer memory together with the reports of human observers. The results obtained using this highly novel and rigorous approach are very different from those obtained using simple observational techniques, and suggest the best model of TD in rats is the tiny tremorous oscillations of the lips which rats begin to show only after many months of chronic neuroleptic administration and which are largely undetected by the naked eye. We now propose to further investigate this promising animal model of tardive dyskinesia by clarifying, through further computer analysis and amplified recording procedures, what the small oral oscillations actually represent. Other studies will access whether different regimens of neuroleptic administration alter the development of persistant side effects of chronic neuroleptics, including whether fluctuating or very steady levels of neuroleptics are more prone to induce the disorder. We also propose to compare the extent to which various classes of neuroleptics (including several novel, atypical neuroleptics) induce this disorder, and whether the concurrent administration of selected dopamine stimulants (D1 v. D2 agonists) facilitate or hinder the development of the syndrome. Other studies will further investigate the pharmacology of oral movements using drugs which act on dopamine, or acetylcholine, or GABA systems within the brain, and then compare effects of these compounds on TD-like vacuous OMs in chronic animals. Detailed regional, autoradiographic studies of receptor binding will be conducted on chronic neuroleptic animals at the completion of these experiments so that varying degrees of symptomatology can be correlated with regional alterations in brain biochemistry. These experiments address an important research issue involving a widespread iatrogenic disorder. The experimental questions addressed in this proposal will probably only be answered in the near future using an animal model such as that proposed here.