M1 and M4 mAChRs in striatum-implication in treatment of movement disorders

纹状体中的 M1 和 M4 mAChR 对运动障碍治疗的影响

• 批准号: 8247009
• 负责人: ZIXIU XIANG
• 金额: $ 33.44万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247009
• 关键词: Acetylcholine; Acute; Address; Adverse effects; Agonist; Allosteric Site; Animal Model; Animals; Anti-Cholinergics; Antiparkinson Agents; Applications Grants; Basal Ganglia; Behavioral; Brain; Catalepsy; Cell Nucleus; Cells; Chemosensitization; Clinic; Clinical; Code; Corpus striatum structure; Development; Disease; Dopamine; Dystonia; Functional disorder; Genes; Goals; Haloperidol; Human; Hyperactive behavior; Individual; Interneurons; Knockout Mice; Lead; Ligands; Long-Term Potentiation; Mediating; Mental Depression; Motor; Movement Disorders; Mus; Muscarinic Acetylcholine Receptor; Muscarinic M1 Receptor; Muscarinics; N-Methyl-D-Aspartate Receptors; Neurons; Parkinson Disease; Patients; Peripheral; Pharmaceutical Preparations; Physiological; Play; Rattus; Receptor Activation; Regulation; Replacement Therapy; Reserpine; Rodent Model; Role; Series; Signal Transduction; Site; Slice; Source; Structure; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic Effect; Transgenic Mice; Up-Regulation; base; cholinergic; human CHRM4 protein; improved; loss of function; motor control; motor deficit; neuronal excitability; novel; patch clamp; public health relevance; receptor; tool; transmission process

DESCRIPTION (provided by applicant): Anticholinergic drugs, such as the muscarinic acetylcholine receptor (mAChR) antagonist trihexyphenidyl, were the first accepted treatment for Parkinson's disease (PD) and are still in clinic use for this disorder and are among the most effective drugs available for treatment of dystonia. However, clinical utility of these compounds is limited by the severe central and peripheral adverse effects that are likely mediated by mAChR subtypes that are not related to the treatment of these disorders. In addition, the site of action of anticholinergics in the treatment of PD and dystonia is largely unknown. It is commonly believed that both PD and dystonia are circuit disorders involving the basal ganglia (BG) dysfunction and also considered as hypercholinergic disorders. Evidence suggests that M1 and M4 are the most abundant mAChR subtypes expressed in principal projection neurons in the striatum, a major input structure in the BG. Hyperactivity of striatal projection neurons (also termed medium spiny neurons, MSNs) is postulated to be associated with motor deficits in PD and dystonia and increased cholinergic signaling in the striatum has also been implicated in PD and certain forms of dystonia. Based on net excitation of MSNs by mAChR activation, drugs that selectively block mAChR subtypes that mediate the net excitation of striatal MSNs, but devoid of activity for other subtypes, might be expected to have therapeutic effects on PD and dystonia without undesired adverse effects. However, due to lack of highly selective mAChR ligands, definitive determination of the individual mAChR subtypes involved in physiological and pathophysiological functions in the striatum has not been possible until recently. Now we have developed a series of novel compounds that display unprecedented selectivity for either M1 or M4 subtype with no detectable activity at any other mAChR subtypes. In this proposal, we will take advantage of these novel, highly selective mAChR ligands and transgenic mice in which gene coding a specific mAChR subtype is deleted, to definitively determine the roles of M1 and M4 in regulating physiological functions of striatal MSNs. Specifically, we will rigorously test the hypothesis that 1) M1 and M4 mACh are involved in modulation of neuronal excitability in MSNs; 2) M1 mAChR activation potentiates NMDA receptor currents in MSNs; 3) M1 and M4 mAChR play important roles in modulation of transmission and long-term plasticity at corticostriatal synapses in MSNs. Finally we will determine the ability of selective M1 antagonist and M4 potentiator to alleviate motor deficits of rodent models of PD and dystonia. The results of these studies will provide critical new information regarding the different roles of M1 and M4 mAChR subtypes in physiological and pathophysiological functions in the striatum and provide the basis for the development of improved anticholinergic therapies for PD, dystonia and other movement disorders that could be devoid of the severe adverse effects. PUBLIC HEALTH RELEVANCE: Anticholinergic drugs, such as the muscarinic acetylcholine receptor (mAChR) antagonist trihexyphenidyl, are among the most effective drugs available for treatment of Parkinson's disease (PD) and dystonia, while clinical utility of these compounds is limited by the severe central and peripheral adverse effects that are likely associated with non-selectivity of these compounds that block mAChR subtypes unrelated to the treatment of these disorders. We have developed a series of novel, highly selective mAChR ligands for either M1 or M4 subtypes, both of which are most abundant mAChR subtypes in the striatum, a brain structure involved in motor control and movement disorders including PD and dystonia. Our goal for this project is using these highly selective ligands to gain a detailed understanding of the physiological roles of M1 and M4 mAChR subtypes in the striatum, and to test the ability of some of these compounds to alleviate motor deficits in animal models of PD and dystonia, and to provide critical new information that may lead to development of new drugs for the treatment of these disorders that could be devoid of the severe adverse effects.

描述（由申请人提供）：抗胆碱能药物，如muscarinic acetylcholine receptor （mAChR）拮抗剂trihexyphenidyl，是最早被接受的帕金森病（PD）治疗药物，目前仍在临床上用于治疗该疾病，并且是治疗肌张力障碍最有效的药物之一。然而，这些化合物的临床应用受到严重的中枢和外周不良反应的限制，这些不良反应可能由与这些疾病治疗无关的mAChR亚型介导。此外，抗胆碱能药物在帕金森病和肌张力障碍治疗中的作用部位在很大程度上是未知的。一般认为PD和肌张力障碍都是涉及基底神经节（BG）功能障碍的电路障碍，也被认为是高胆碱能障碍。有证据表明，M1和M4是最丰富的mAChR亚型，表达在纹状体的主要投射神经元中，纹状体是BG的主要输入结构。纹状体投射神经元（也称为中棘神经元，msn）的过度活跃被认为与帕金森病和肌张力障碍的运动缺陷有关，纹状体中胆碱能信号的增加也与帕金森病和某些形式的肌张力障碍有关。基于mAChR激活对msn的净兴奋，选择性阻断介导纹状体msn净兴奋的mAChR亚型，但对其他亚型缺乏活性的药物，可能有望对PD和肌张力障碍产生治疗作用，而不会产生不良反应。然而，由于缺乏高选择性的mAChR配体，直到最近才可能明确确定纹状体中参与生理和病理生理功能的单个mAChR亚型。现在，我们已经开发了一系列新的化合物，对M1或M4亚型表现出前所未有的选择性，而对任何其他mAChR亚型没有检测到活性。在本研究中，我们将利用这些新型的、高选择性的mAChR配体和基因编码特定mAChR亚型被删除的转基因小鼠，明确确定M1和M4在调节纹状体msn生理功能中的作用。具体来说，我们将严格验证以下假设：1)M1和M4 mACh参与了msnn神经元兴奋性的调节；2) M1 mAChR激活增强了mmsn中的NMDA受体电流；3) M1和M4 mAChR在msn皮质纹状体突触的传递和长期可塑性调节中发挥重要作用。最后，我们将确定选择性M1拮抗剂和M4增强剂减轻PD和肌张力障碍啮齿动物模型运动缺陷的能力。这些研究结果将为M1和M4 mAChR亚型在纹状体生理和病理生理功能中的不同作用提供重要的新信息，并为PD、肌张力障碍和其他运动障碍的改进抗胆碱能治疗提供基础，这些治疗可能没有严重的不良反应。