DEVELOPMENT OF A MONKEY DYSTONIA MODEL

这个子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 肌张力障碍是一种致残性疾病，治疗选择不满意。 由于观察到肌张力障碍（而不是帕金森综合征）经常伴随着年轻患者多巴胺代谢紊乱的状态，这些研究评估了多巴胺耗竭对幼猴的影响。 在报告期间，我们完成了对三只接受每周注射MPTP治疗的幼猴的观察。 尽管累积MPTP剂量超过用于诱导帕金森病的老年动物的剂量的三倍，但动物没有发生显著的帕金森病或肌张力障碍。 我们还研究了另外两只较年轻的动物，它们在一个月内接受了较高剂量的MPTP治疗。 两人均出现间歇性颈部、躯干和四肢肌张力障碍。 其中一人还出现了轻度帕金森症。作为肌张力障碍的典型表现，行为激活加剧了异常姿势。 在发展为帕金森综合征的动物中，这与肌张力障碍的严重程度弱相关。 我们还在分析组织学结果。 一项关于多巴胺耗竭标记物（酪氨酸羟化酶和多巴胺转运蛋白染色）的研究表明，有症状的猴子比无症状的猴子表现出更明显的纹状体多巴胺能损失，并且患有肌张力障碍的幼猴纹状体多巴胺能神经支配的损失至少与帕金森病成年动物一样严重。 这些结果提供了证据表明，当在很小的年龄进行消耗性干预时，多巴胺消耗会导致肌张力障碍。 我们目前正在研究这些动物中胆碱能和胆碱能标记物的分布。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Dystonia is a disabling condition with unsatisfactory treatment choices. Motivated by the observation that dystonia (and not parkinsonism) frequently accompanies states of disturbed dopamine metabolism in young patients, these studies assess the effects of dopamine depletion in infant monkeys. During the reporting period, we completed observations in three infant monkeys which were treated with weekly injections of MPTP. Despite the fact that the cumulative MPTP doses surpassed those used in older animals for the induction of parkinsonism threefold, the animals did not develop significant parkinsonism or dystonia. We also studied two additional younger animals which were treated with higher doses of MPTP over the course of one month. Both developed intermittent neck, trunk and extremity dystonia. One of them also developed mild parkinsonism. As is typical for dystonia, behavioral activation exacerbated abnormal posturing. In the animal that developed parkinsonism, this was weakly correlated with the severity of dystonia. We are still analyzing the histological results. A study of markers of dopamine depletion (stains for tyrosine hydroxylase and the dopamine transporter) showed that symptomatic monkeys showed more pronounced striatal dopaminergic loss than asymptomatic monkeys and that the loss of striatal dopaminergic innervation in the infant monkeys with dystonia was at least as severe as that in parkinsonian adult animals. These results provide evidence that dopamine depletion can lead to dystonia when the depleting intervention occurs at a very young age. We are currently in the process of studying the distribution of cholinergic and serotonergic markers in these animals.