MOTOR EFFECTS OF PDE10A INHIBITORS IN PRIMATES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 环核苷酸磷酸二酯酶10A（PDE 10A）在纹状体中高度表达，在纹状体中其参与与认知和运动功能相关的信号传导机制。 PDE 10A定位于中等多刺神经元（MSN）的细胞膜，其是驱动纹状体输出的投射神经元，并水解cAMP和cGMP的环状磷酸二酯键，这导致纹状体输出途径中的信号转导的调节。 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PDE 10A抑制剂已被合成，这些药物的临床前试验已显示出对精神分裂症的显著治疗潜力。 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PDE 10A抑制剂的运动效应尤为重要。 因此，在本项目中，我们将研究TP-10，一种选择性PDE 10A抑制剂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这些药物在精神分裂症临床应用的潜在副作用，还可能使我们发现PDE 10A抑制剂的替代应用。 例如，PDE 10A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某些异常。 因此，可以想象PDE 10A抑制剂可能显示出抗帕金森病疗效。

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.