Gomeza J, Zhang L, Kostenis E, Felder C, Bymaster F, Brodkin J, Shannon H, Xia B, Deng C, Wess J
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10483-8. doi: 10.1073/pnas.96.18.10483.
Muscarinic acetylcholine receptors (M(1)-M(5)) regulate many key functions of the central and peripheral nervous system. Primarily because of the lack of receptor subtype-selective ligands, the precise physiological roles of the individual muscarinic receptor subtypes remain to be elucidated. Interestingly, the M(4) receptor subtype is expressed abundantly in the striatum and various other forebrain regions. To study its potential role in the regulation of locomotor activity and other central functions, we used gene-targeting technology to create mice that lack functional M(4) receptors. Pharmacologic analysis of M(4) receptor-deficient mice indicated that M(4) receptors are not required for muscarinic receptor-mediated analgesia, tremor, hypothermia, and salivation. Strikingly, M(4) receptor-deficient mice showed an increase in basal locomotor activity and greatly enhanced locomotor responses (as compared with their wild-type littermates) after activation of D1 dopamine receptors. These results indicate that M(4) receptors exert inhibitory control on D1 receptor-mediated locomotor stimulation, probably at the level of striatal projection neurons where the two receptors are coexpressed at high levels. Our findings offer new perspectives for the treatment of Parkinson's disease and other movement disorders that are characterized by an imbalance between muscarinic cholinergic and dopaminergic neurotransmission.
毒蕈碱型乙酰胆碱受体（M(1)-M(5)）调节中枢和外周神经系统的许多关键功能。主要由于缺乏受体亚型选择性配体，各个毒蕈碱受体亚型的确切生理作用仍有待阐明。有趣的是，M(4)受体亚型在纹状体和其他各种前脑区域大量表达。为了研究其在调节运动活动和其他中枢功能中的潜在作用，我们使用基因靶向技术创建了缺乏功能性M(4)受体的小鼠。对M(4)受体缺陷小鼠的药理学分析表明，毒蕈碱受体介导的镇痛、震颤、体温过低和唾液分泌不需要M(4)受体。令人惊讶的是，M(4)受体缺陷小鼠的基础运动活动增加，并且在D1多巴胺受体激活后运动反应大大增强（与其野生型同窝小鼠相比）。这些结果表明，M(4)受体可能在纹状体投射神经元水平上对D1受体介导的运动刺激发挥抑制作用，这两种受体在该水平上高水平共表达。我们的发现为治疗帕金森病和其他以毒蕈碱胆碱能和多巴胺能神经传递失衡为特征的运动障碍提供了新的视角。
