MOTOR EFFECTS OF PDE10A INHIBITORS IN PRIMATES

PDE10A 抑制剂对灵长类动物的运动影响

• 批准号: 8357478
• 负责人: Stella M Papa
• 金额: $ 4.12万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357478
• 关键词: Adverse effects; Antipsychotic Agents; Automobile Driving; Behavior; Brain; Cell membrane; Clinical; Cognitive; Corpus striatum structure; Cyclic AMP; Cyclic GMP; Cyclic Nucleotides; Drug usage; Funding; Goals; Grant; Lead; Macaca; Metabolic; Monkeys; Motor; Movement; National Center for Research Resources; Neurons; Output; Pathway interactions; Pharmaceutical Preparations; Posture; Preclinical Testing; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Risperidone; Schizophrenia; Signal Transduction; Source; Therapeutic; Time; United States National Institutes of Health; cost; inhibitor/antagonist; phosphodiester; phosphoric diester hydrolase

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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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。 在本项目中，我们计划研究MP-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。 该项目已扩展到评价常见抗精神病药利培酮在相同范例中与MP-10进行比较的效果。 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。