Dean B, Bymaster F P, Scarr E
The Rebecca L. Cooper Research Laboratories, The Mental Health Research Institute of Victoria, Parkville, Victoria, Australia.
Curr Mol Med. 2003 Aug;3(5):419-26. doi: 10.2174/1566524033479654.
An increasing body of evidence suggests that the muscarinic receptors may present a potential therapeutic target for the treatment of schizophrenia. This argument is supported by studies using postmortem CNS tissue and a neuroimaging study that have shown there are regionally specific decreases in selective muscarinic receptors in the CNS of subjects with schizophrenia. This raises the possibility that drugs specific to individual muscarinic receptors could have beneficial effects on the symptoms of schizophrenia, a posit supported by studies in receptor knockout/knockdown mice where it has been shown that specific behaviours affected by schizophrenia are also abnormal in mice lacking a single muscarinic receptor. Moreover, drugs have been synthesised that are partial agonists at muscarinic receptors and these drugs have been shown to improve the behavioural deficits in humans which are modulated by the muscarinic receptor family. The widespread distribution of muscarinic receptors in the human CNS and the receptor specific changes identified in postmortem CNS from subjects with schizophrenia would suggest that drugs targeting specific muscarinic receptors would also need to partition into selected CNS regions to achieve optimal responses. Some existing compounds show regional selectivity for the same muscarinic receptor in different CNS regions, suggesting that this characteristic could be engineered into muscarinic receptor targeting drugs. This review presents data from diverse areas of research to argue that it is now imperative that the therapeutic potential of manipulating the activity of muscarinic receptors for the treatment of schizophrenia is fully explored.
越来越多的证据表明，毒蕈碱受体可能是治疗精神分裂症的一个潜在治疗靶点。使用死后中枢神经系统组织的研究和一项神经影像学研究支持了这一观点，这些研究表明，精神分裂症患者中枢神经系统中选择性毒蕈碱受体存在区域特异性减少。这就增加了一种可能性，即针对单个毒蕈碱受体的药物可能对精神分裂症症状有有益影响，这一观点得到了受体敲除/敲低小鼠研究的支持，在这些研究中，已表明受精神分裂症影响的特定行为在缺乏单个毒蕈碱受体的小鼠中也异常。此外，已经合成了作为毒蕈碱受体部分激动剂的药物，并且这些药物已被证明可改善人类中由毒蕈碱受体家族调节的行为缺陷。毒蕈碱受体在人类中枢神经系统中的广泛分布以及在精神分裂症患者死后中枢神经系统中发现的受体特异性变化表明，靶向特定毒蕈碱受体的药物也需要分布到选定的中枢神经系统区域以实现最佳反应。一些现有化合物对不同中枢神经系统区域中的同一毒蕈碱受体表现出区域选择性，这表明这一特性可设计到靶向毒蕈碱受体的药物中。本综述展示了来自不同研究领域的数据，以论证现在必须充分探索操纵毒蕈碱受体活性用于治疗精神分裂症的治疗潜力。
