DRUG HOLIDAYS IN CHRONIC NEUROLEPTICS: AN ANIMAL MODEL

迟发性运动障碍在接受治疗的人类中占相当大的比例 长期服用抗精神病药。尽管一些抗精神病药物可能会有 减少了引发这种疾病的倾向，似乎有可能 所有的抗精神病药物，如果在相似的时期给予相同的量，将会 有很大的风险引发这种综合症。这导致了 临床医生试图通过以下方式降低迟发性运动障碍的发生率 给予定期的戒毒间隔，或“戒毒假期”。然而， 回溯性的临床研究非常不清楚这种做法是否 是有益的还是实际上有害的，动物研究表明药物 假期可以有积极的影响，也可以有消极的影响，这取决于 精确的实验细节。 这里建议使用动物模型来研究，准确的是 抗精神病药物的给药方案，促进或阻碍 慢性抗精神病药物持续性副作用的研究进展。首先，我们 将完善一种方法，方便地提供非常稳定的 长期给大鼠注射氟哌啶醇，并发展出一种自动化的 精确量化和识别的子组件的程序 慢性给药大鼠的“空腹咀嚼运动” 神经镇静剂。使用这些程序，药物的剂量和长度的作用 行政决定了这些异常的发展历程 停药后的口腔行为及其持久性将被 学习。 在此基础上，提出了确定具体实验条件的建议。 在服用抗精神病药物的过程中，哪些“药物假期”是有益的？ 长期影响。这些研究将包括确定 最佳的药物假期长度、时间以及突然和间接的比较 逐步戒毒。还建议确定是否存在 慢性抗精神病药物的持续性副作用有不同程度 当这些药物长期给药以诱导稳定的血清时 水平(与仓库注入时一样)与波动较大的水平 由口服引起的。 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。中提出的试验性问题 这项提议可能只会在不久的将来通过使用 像这里提出的那样的动物模型。

Tardive dyskinesia develops in a substantial proportion of humans treated with chronic neuroleptics. Although some antipsychotic drugs may have a lessened propensity for inducing this disorder, it appears possible that all neuroleptics, if given in similar amounts for similar periods, will carry a substantial risk for inducing this syndrome. This has led clinicians to attempt to decrease the incidence of tardive dyskinesia by giving periodic drug-free intervals, or "drug holidays". However, retrospective clinical studies are very unclear as to whether this practice is beneficial or actually deleterious, and animal studies suggest drug holidays can have either positive or negative effects depending upon precise experimental details. It is proposed here to study, using an animal model, what are the precise regimens of neuroleptic administration which facilitate or hinder the development of persisting side-effects of chronic neuroleptics. First we will perfect a method for conveniently delivering very constant levels of haloperidol to rats over prolonged periods of time and develop an automated procedure for precisely quantifying and identifying subcomponents of the "vacuous chewing movements" which develop in rats administered chronic neuroleptics. Using these procedures the role of dosage and length of drug administration in determining the course of development of these abnormal oral behaviors and their persistance following drug discontinuation will be studied. It is then proposed to determine the exact experimental conditions under which "drug holidays" in neuroleptic administration can have beneficial long-term effects. Included in these studies will be the determination of optimal drug holiday length, timing, and a comparison of abrupt versus gradual drug withdrawal. It is also proposed to determine whether there are differing degrees of persisting side-effects of chronic neuroleptics when these drugs are chronically administered so as to induce steady serum levels (as occur with depot injections) versus the more fluctuating levels induced by oral administration. 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.