DRUG HOLIDAYS IN CHRONIC NEUROLEPTICS: AN ANIMAL MODEL

慢性神经抑郁症的药物假期：动物模型

• 批准号: 3377775
• 负责人: GAYLORD D ELLISON
• 金额: $ 10.32万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 1991-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3377775
• 关键词: antipsychotic agents; brain metabolism; dosage; drug adverse effect; drug delivery systems; drug withdrawal; ethology; haloperidol; high performance liquid chromatography; laboratory rat; psychopharmacology; tardive dyskinesia

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.

迟发性运动障碍（TD）是一种严重的医源性疾病， 在接受慢性药物治疗的精神分裂症患者中 神经抑制剂 这个实验室开发了一种非常独特的 迟发性运动障碍动物模型的基础上， 系统，其中大鼠口腔运动（OM）的测量被 与报告一起直接存入计算机内存 人类观察者。 使用这种高度新颖的方法获得的结果 和严格的方法是非常不同的， 使用简单的观察技术，并建议最佳模型 大鼠TD的一个重要特征是嘴唇的轻微震颤， 老鼠开始显示只有经过许多个月的慢性精神抑制剂 这些物质在给药过程中是不可见的，并且肉眼基本上无法检测到。 我们现在建议进一步研究这种有前途的动物 迟发性运动障碍的模型，通过进一步澄清， 计算机分析和放大录音程序，什么 实际上代表了口腔振动。 其他研究将 了解不同的抗精神病药物给药方案 改变慢性药物持续副作用的发展， 神经安定药，包括水平波动还是非常稳定 更容易诱发这种疾病 我们也 建议比较各种类别的 精神抑制剂（包括几种新型的非典型精神抑制剂）诱导 这种疾病，以及是否同时给予 选择的多巴胺兴奋剂（D1与D2激动剂）促进或 阻碍综合征的发展。 其他研究将 进一步研究口腔运动的药理学， 作用于多巴胺、乙酰胆碱或GABA系统的药物 然后比较这些化合物对 慢性动物中的TD样空洞OM。 详细的区域， 受体结合的放射自显影研究将在 慢性神经阻滞剂动物在完成这些 实验，使不同程度的神经病学可以 与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， 广泛的医源性疾病 实验问题 在这个建议中所涉及的问题可能只会在 不久的将来，使用动物模型，如这里提出的。