MOTOR EFFECTS OF PDE10A INHIBITORS IN PRIMATES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 环核苷酸磷酸二酯酶10A(PD10A)在纹状体高表达，参与与认知和运动功能相关的信号机制。近年来，选择性PDE10A抑制剂已经被合成，这些药物的临床前试验显示出对精神分裂症的巨大治疗潜力。 目前，这些药物对其他行为领域的影响还不太清楚。与其他抗精神病药物一样，评估PDE10A抑制剂的运动效果尤为重要。这些影响还没有完全确定，我们将在非人类灵长类动物身上进行研究。了解这种运动效应不仅有助于我们预测临床使用这些药物治疗精神分裂症的潜在副作用，而且还可能引导我们发现PDE10A抑制剂的替代应用。最近的生理学数据表明，PDE10A可能主要在纹状体神经元的某些亚群中表达，然后PDE10A抑制剂可以选择性地针对这些亚群。 纹状体神经元亚群活动之间的失衡是帕金森氏病等运动障碍的病理生理学的核心。因此，可以想象，PDE10A抑制剂可能对帕金森症状具有疗效。在这个项目中，我们将研究选择性PDE10A抑制剂TP-10在灵长类动物中的运动效应。这是一个新启动的项目。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The cyclic nucleotide phosphodiesterase 10A (PD10A) is highly expressed in the striatum where it participates in signaling mechanisms related to cognitive and motor function. In recent years, selective PDE10A inhibitors have been synthesized, and preclinical tests of these agents have shown significant therapeutic potential for schizophrenia. At this time, the effects of these drugs on other realms of behavior are less clear. As with other antipsychotic drugs, it will be particularly important to evaluate the motor effects of PDE10A inhibitors. These effects are not fully characterized, and we will study them in non-human primates. Knowing such motor effects would not only help us predict potential side effects of the clinical use of these drugs in schizophrenia, but may also lead us to discover alternative applications for PDE10A inhibitors. As indicated by recent physiology data, PDE10A may be expressed predominantly in certain subpopulations of striatal neurons that could then be selectively targeted by PDE10A inhibitors. Imbalances between the activities of neuronal subpopulations in the striatum are at the core of the pathophysiology of movement disorders such as Parkinson's disease. It is therefore conceivable that PDE10A inhibitors may show efficacy against parkinsonian symptoms. In this project, we will characterize the motor effects of TP-10, a selective PDE10A inhibitor, in primates. This is a newly activated project.