PHARMACOLOGIC STUDY ON MODELS OF TARDIVE DYSKINESIA

迟发性运动障碍模型的药理学研究

• 批准号: 2267669
• 负责人: RICHARD M KOSTRZEWA
• 金额: $ 8.66万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-06-01 至 1995-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2267669
• 关键词: 6 hydroxydopamine; abnormal involuntary movement; biomedical equipment purchase; computers; disease /disorder model; dopamine receptor; inhibitor /antagonist; laboratory rat; neuropharmacology; newborn animals; oral behavior; stimulant /agonist; tardive dyskinesia; video recording system

There exists a need for an animal model that would replicate some of the characteristics of the oral dyskinesias that occur in tardive dyskinesia, a long-lived motor abnormality that arises after excessive use of neuroleptic agents in humans. This model would be useful to investigate mechanisms that may be involved in tardive dyskinesia, and to test agents that have a potential to prevent or even reverse the motor or biochemical abnormalities that occur in tardive dyskinesia. Testing equipment is available for measuring the frequency of mouth openings, the amplitude of mouth movement, and the rates of mouth opening and closing. The technology uses frame grabbers to record the relative positions of upper to lower jaws at increments of 1/60 sec. With a computer assist, the data are recorded as amplitude of mouth opening vs. time. Fast fourier transformation provides an energy spectrum of the oral activity, so that comparison can be made with the low frequency mouth movements of tardive dyskinesia. The project is designed to set up this equipment in the laboratory to determine the oral characteristics of rats that have abnormal oral activity. We have found that there is a 10 fold increase in dopamine D2 antagonist-induced oral activity in adult rats that received a neonatal 6-hydroxydopamine lesion of the dopaminergic fibers in the brain. A similar enhancement of oral activity was produced by a Dl agonist in these rats. In this project we shall determine how the features of the oral activity in these and related models, compare with that shown for tardive dyskinesia. The Bmax and Kd for Dl and D2 receptors in the striatum will be determined, as well as the ratio of high and low affinity forms of each receptor type. Biochemical determination of the status of the receptor complex will be made for potentially useful models. The final study will explore the possible effects of a peptide that modulates the dopamine receptor, and which could possibly be useful in treatment of tardive dyskinesia. A new model to investigate aspects of tardive dyskinesia would be of immense value. The proposed model is of added benefit since the susceptibility for induction of oral activity is seemingly permanent.

需要一种能够复制某些特征的动物模型 迟发性运动障碍中发生的口腔运动障碍的特征， 过度使用后出现的长期运动异常 人类的精神安定剂。 该模型对于研究很有用 可能涉及迟发性运动障碍的机制，并测试药物 有可能阻止甚至逆转电机或生化 迟发性运动障碍中发生的异常。 检测设备有 可用于测量张口频率、张口幅度 嘴巴运动，以及张嘴和闭嘴的速率。 技术 使用图像采集卡记录上下颌的相对位置 以 1/60 秒的增量 在计算机辅助下，记录数据 作为张嘴幅度与时间的关系。 快速傅立叶变换 提供口腔活动的能谱，以便进行比较 由迟发性运动障碍的低频口腔运动引起。 这 项目旨在在实验室中设置该设备以确定 口腔活动异常的大鼠的口腔特征。 我们有 发现多巴胺 D2 拮抗剂诱导的作用增加了 10 倍 接受新生 6-羟基多巴胺的成年大鼠的口腔活动 大脑中多巴胺能纤维的损伤。 类似的增强 D1激动剂在这些大鼠中产生口服活性。 在这个项目中 我们将确定这些和中的口头活动的特征如何 相关模型，与迟发性运动障碍的模型进行比较。 最大体重 纹状体中 D1 和 D2 受体的 Kd 和 Kd 也将被确定 作为每种受体类型的高亲和力形式和低亲和力形式的比率。 受体复合物状态的生化测定将是 为潜在有用的模型而制作。 最终研究将探讨 调节多巴胺受体的肽的可能作用，以及 这可能有助于治疗迟发性运动障碍。 一个新的 研究迟发性运动障碍各个方面的模型将具有巨大的意义 价值。 所提出的模型具有额外的好处，因为对 口腔活动的诱导似乎是永久性的。

项目成果

Enhanced pilocarpine-induced oral activity responses in neonatal 6-OHDA treated rats.

增强毛果芸香碱诱导的新生 6-OHDA 治疗大鼠的口腔活动反应。

• DOI: 10.1016/0091-3057(93)90534-z
• 发表时间: 1993
• 期刊: Pharmacology, biochemistry, and behavior
• 作者: Kostrzewa,RM;Neely,D
• 通讯作者: Neely,D

Age-dependence of a 6-hydroxydopamine lesion on SKF 38393- and m-chlorophenylpiperazine-induced oral activity responses of rats.

• DOI: 10.1016/0165-3806(93)90126-u
• 发表时间: 1993-11
• 期刊: Brain research. Developmental brain research
• 作者: R. Kostrzewa;R. Brus;K. Perry;R. Fuller

Ontogenetic quinpirole treatment induces vertical jumping activity in rats.

个体发生喹吡罗治疗可诱导大鼠的垂直跳跃活动。

• DOI: 10.1016/0014-2999(93)90992-q
• 发表时间: 1993
• 期刊: European journal of pharmacology
• 影响因子: 5
• 作者: Kostrzewa,RM;Guo,J;Kostrzewa,FP
• 通讯作者: Kostrzewa,FP

Supersensitization of the oral response to SKF 38393 in neonatal 6-hydroxydopamine-lesioned rats is eliminated by neonatal 5,7-dihydroxytryptamine treatment.

新生 6-羟基多巴胺损伤大鼠对 SKF 38393 口服反应的超敏化可通过新生 5,7-二羟基色胺治疗消除。

• 发表时间: 1994
• 期刊: The Journal of pharmacology and experimental therapeutics
• 作者: Brus,R;Kostrzewa,RM;Perry,KW;Fuller,RW
• 通讯作者: Fuller,RW

Modeling tardive dyskinesia: predictive 5-HT2C receptor antagonist treatment.

迟发性运动障碍建模：预测性 5-HT2C 受体拮抗剂治疗。

• DOI: 10.1007/bf03033481
• 发表时间: 2007
• 期刊: Neurotoxicity research
• 影响因子: 3.7
• 作者: Kostrzewa,RichardM;Huang,Nuo-Yu;Kostrzewa,JohnP;Nowak,Przemyslaw;Brus,Ryszard
• 通讯作者: Brus,Ryszard