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(PDE10A)在纹状体高表达，参与与认知和运动功能相关的信号机制。PDE10A定位于驱动纹状体输出的中棘神经元(MSN)的细胞膜上，并水解cAMP和cGMP的环磷酸二酯键，从而调节纹状体输出通路中的信号转导。这些通路中的信号机制是控制姿势和运动的关键。 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。 因此，在本项目中，我们将研究选择性PDE10A抑制剂TP-10对正常猕猴运动行为和脑代谢活动的影响。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。例如，PDE10A可能主要在纹状体神经元的某些亚群中表达。 阻断这些受体可能会逆转帕金森症患者纹状体功能的一些异常。因此，可以想象，PDE10A抑制剂可能显示出抗帕金森症的疗效。

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 (PDE10A) is highly expressed in the striatum where it participates in signaling mechanisms related to cognitive and motor function. PDE10A is localized to the cell membrane of medium spiny neurons (MSNs) that are the projection neurons driving the striatal output, and hydrolyzes cyclic phosphodiester bonds of cAMP and cGMP, which results in modulation of signal transduction in striatal output pathways. Signaling mechanisms in these pathways is key to the control of posture and movement. 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. In this project, we will therefore study the effects of TP-10, a selective PDE10A inhibitor on motor behavior and brain metabolic activity in normal macaque monkeys. 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. For instance, PDE10A may be predominantly expressed in certain subpopulations of striatal neurons. Blocking these receptors may revert some of the abnormalities of striatal function in parkinsonism. It is, therefore, conceivable that PDE10A inhibitors may show antiparkinsonian efficacy.