MOTOR EFFECTS OF PDE10A INHIBITORS IN PRIMATES

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。 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。在本项目中，我们计划研究选择性PDE10A抑制剂MP-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。 该项目已扩大到评估普通抗精神病药物利培酮在相同范例中的效果，以便与MP-10进行比较。这些研究的目的是确定MP-10相对于目前用于治疗精神分裂症的药物的治疗优势。

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. 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 are 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 planned to study the effects of MP-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. The project has been extended to evaluate the effects of the common antipsychotic risperidone in the same paradigms for comparison with MP-10. The goal of these studies is to determine the therapeutic advantages of MP-10 with respect to drugs used currently for the therapy of schizophrenia.