Dencker Ditte, Thomsen Morgane, Wörtwein Gitta, Weikop Pia, Cui Yinghong, Jeon Jongrye, Wess Jürgen, Fink-Jensen Anders
Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen, University of Copenhagen, DK-2100 Copenhagen, Denmark.
ACS Chem Neurosci. 2012;3(2):80-89. doi: 10.1021/cn200110q.
The neurotransmitter dopamine plays important roles in modulating cognitive, affective, and motor functions. Dysregulation of dopaminergic neurotransmission is thought to be involved in the pathophysiology of several psychiatric and neurological disorders, including schizophrenia, Parkinson's disease and drug abuse. Dopaminergic systems are regulated by cholinergic, especially muscarinic, input. Not surprisingly, increasing evidence implicates muscarinic acetylcholine receptor-mediated pathways as potential targets for the treatment of these disorders classically viewed as "dopamine based". There are five known muscarinic receptor subtypes (M(1) to M(5)). Due to their overlapping expression patterns and the lack of receptor subtype-specific ligands, the roles of the individual muscarinic receptors have long remained elusive. During the past decade, studies with knock-out mice lacking specific muscarinic receptor subtypes have greatly advanced our knowledge of the physiological roles of the M(1)-M(5) receptors. Recently, new ligands have been developed that can interact with allosteric sites on different muscarinic receptor subtypes, rather than the conventional (orthosteric) acetylcholine binding site. Such agents may lead to the development of novel classes of drugs useful for the treatment of psychosis, drug abuse and Parkinson's disease. The present review highlights recent studies carried out using muscarinic receptor knock-out mice and new subtype-selective allosteric ligands to assess the roles of M(1), M(4), and M(5) receptors in various central processes that are under strong dopaminergic control. The outcome of these studies opens new perspectives for the use of novel muscarinic drugs for several severe disorders of the CNS.
神经递质多巴胺在调节认知、情感和运动功能方面发挥着重要作用。多巴胺能神经传递的失调被认为与多种精神和神经疾病的病理生理学有关，包括精神分裂症、帕金森病和药物滥用。多巴胺能系统受胆碱能输入的调节，尤其是毒蕈碱能输入。毫不奇怪，越来越多的证据表明，毒蕈碱型乙酰胆碱受体介导的途径是治疗这些传统上被视为“基于多巴胺”的疾病的潜在靶点。已知有五种毒蕈碱受体亚型（M(1)至M(5)）。由于它们重叠的表达模式以及缺乏受体亚型特异性配体，单个毒蕈碱受体的作用长期以来一直难以捉摸。在过去十年中，对缺乏特定毒蕈碱受体亚型的基因敲除小鼠的研究极大地推进了我们对M(1)-M(5)受体生理作用的认识。最近，已经开发出了新的配体，它们可以与不同毒蕈碱受体亚型的变构位点相互作用，而不是与传统的（正构）乙酰胆碱结合位点相互作用。这类药物可能会导致开发出用于治疗精神病、药物滥用和帕金森病的新型药物。本综述重点介绍了最近使用毒蕈碱受体基因敲除小鼠和新的亚型选择性变构配体进行的研究，以评估M(1)、M(4)和M(5)受体在受多巴胺能强烈控制的各种中枢过程中的作用。这些研究结果为使用新型毒蕈碱药物治疗几种严重的中枢神经系统疾病开辟了新的前景。
