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: 8172434
• 负责人: Stella M Papa
• 金额: $ 5.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172434
• 关键词: Adverse effects; Antiparkinson Agents; Antipsychotic Agents; Automobile Driving; Behavior; Brain; Cell membrane; Clinical; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Corpus striatum structure; Cyclic AMP; Cyclic GMP; Cyclic Nucleotides; Drug usage; Funding; Grant; Hydrolysis; Institution; Lead; Macaca; Metabolic; Monkeys; Motor; Movement; Neurons; Output; Parkinsonian Disorders; Pathway interactions; Pharmaceutical Preparations; Posture; Preclinical Testing; Research; Research Personnel; Resources; Schizophrenia; Signal Transduction; Source; Therapeutic; Time; United States National Institutes of Health; inhibitor/antagonist; phosphodiester; phosphoric diester hydrolase; receptor

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 环核苷酸磷酸二酯酶 10A (PDE10A) 在纹状体中高度表达，参与与认知和运动功能相关的信号传导机制。 PDE10A 定位于中型多棘神经元 (MSN) 的细胞膜，MSN 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，从而调节纹状体输出途径中的信号转导。 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抑制剂已被合成，这些药物的临床前测试显示出对精神分裂症的显着治疗潜力。 目前，这些药物对其他行为领域的影响尚不清楚。 与其他抗精神病药物一样，评估 PDE10A 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 PDE10A 抑制剂）对正常猕猴运动行为和大脑代谢活动的影响。 了解此类运动效应不仅可以帮助我们预测这些药物在精神分裂症临床应用中的潜在副作用，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病中纹状体功能的一些异常。 因此，可以想象 PDE10A 抑制剂可能具有抗帕金森病功效。