DRUG HOLIDAYS IN CHRONIC NEUROLEPTICS: AN ANIMAL MODEL

迟发性运动障碍的发展在相当大比例的人类治疗 使用慢性神经安定药。 虽然一些抗精神病药物可能有 减少诱发这种疾病的倾向，似乎有可能， 所有的精神抑制剂，如果在类似的时间内以类似的剂量给药， 有诱发这种综合症的巨大风险。 这导致 临床医生试图通过以下方法降低迟发性运动障碍的发生率 给予定期的无药期，或“药物假期”。 然而，在这方面， 回顾性临床研究非常不清楚这种做法是否 是有益的还是有害的，动物研究表明， 假期可以有积极或消极的影响，这取决于 精确的实验细节 这里建议使用动物模型来研究， 精神抑制剂给药方案，其促进或阻碍 慢性精神抑制剂的持续副作用的发展。 首先我们 将完善一种方便地提供非常恒定水平的 氟哌啶醇对大鼠在较长的一段时间，并开发一个自动 用于精确定量和鉴定药物的亚组分的方法 “空洞的咀嚼运动”，发展在大鼠给予慢性 神经抑制剂 使用这些程序的作用剂量和药物的长度 管理在确定这些异常的发展过程中， 药物停药后的口腔行为及其持续性将 研究了 然后，建议在以下条件下确定确切的实验条件 精神抑制剂给药中的“药物假期” 长期影响。 这些研究将确定 最佳药物假期长度，时间，以及突然与 逐步戒毒。 还建议确定是否有 慢性神经安定药的持续副作用程度不同 当这些药物长期给药以诱导稳定的血清 水平（如贮库型注射液中发生的情况）与波动较大的水平 经口给药诱导。 这些实验解决了一个重要的研究问题， 广泛的医源性疾病 实验问题解决在 这个建议可能只有在不久的将来才能得到回答， 动物模型，如本文所述。

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.