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。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 肌张力障碍是一种有不令人满意的治疗选择的致残状态。由于观察到肌张力障碍(而不是帕金森症)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。 在本报告所述期间，我们完成了对每周注射MPTP治疗的三只幼猴的观察。尽管MPTP的累积剂量是用于诱导帕金森症的老年动物的三倍，但这些动物并没有出现明显的帕金森症或肌张力障碍。我们还研究了另外两只年轻的动物，它们在一个月的时间里接受了更高剂量的MPTP治疗。两人都出现了间歇性颈部、躯干和四肢肌张力障碍。其中一人还患上了轻度帕金森症。与肌张力障碍的典型情况一样，行为激活加剧了不正常的姿势。在患上帕金森症的动物中，这与肌张力障碍的严重程度关系不大。 我们仍在分析组织学结果。一项对多巴胺耗竭标记物(酪氨酸羟基酶和多巴胺转运蛋白的染色)的研究表明，有症状的猴子比没有症状的猴子表现出更明显的纹状体多巴胺能丧失，患有肌张力障碍的幼猴纹状体多巴胺能神经的丧失至少与帕金森成年动物一样严重。这些结果提供了证据，当多巴胺耗竭干预发生在非常年轻的时候，就会导致肌张力障碍。我们目前正在研究胆碱能和5-羟色胺能标记物在这些动物中的分布。

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.