Mayorga A J, Cousins M S, Trevitt J T, Conlan A, Gianutsos G, Salamone J D
Department of Psychology, University of Connecticut, Storrs 06269-1020, USA.
Eur J Pharmacol. 1999 Jan 1;364(1):7-11. doi: 10.1016/s0014-2999(98)00811-5.
Four muscarinic receptor antagonists with varying selectivities for the four pharmacologically-defined muscarinic receptor subtypes (M1-M4) were administered into the lateral ventricle to determine their relative potency in reducing tremulous jaw movements induced by i.p. injection of the muscarinic receptor agonist pilocarpine (4.0 mg/kg). All four muscarinic receptor antagonists reduced tremulous jaw movements in a dose-dependent manner, with the following rank order of potency: scopolamine > methoctramine > or = telenzepine > pirenzepine. This pattern is inconsistent with the rank order of affinity of these agents at the muscarinic M1 receptor, and is consistent with their rank order of affinity at muscarinic M2 or M4 receptors. Because tremulous jaw movements are related to striatal function, and the muscarinic M4 receptor is more predominant than the muscarinic M2 receptor as a post-synaptic receptor in striatum, the present results suggest that pilocarpine induces jaw movements due to muscarinic M4 receptor stimulation. In view of the hypothesized relation between parkinsonism and cholinomimetic-induced jaw movements, these data suggest that a centrally-acting muscarinic M4 receptor antagonist could be useful as an antiparkinsonian agent.
将四种对药理学定义的四种毒蕈碱受体亚型（M1 - M4）具有不同选择性的毒蕈碱受体拮抗剂注入侧脑室，以确定它们在减少腹腔注射毒蕈碱受体激动剂毛果芸香碱（4.0毫克/千克）所诱发的震颤性下颌运动方面的相对效力。所有四种毒蕈碱受体拮抗剂均以剂量依赖性方式减少震颤性下颌运动，效力顺序如下：东莨菪碱>甲溴东莨菪碱>或=替仑西平>哌仑西平。这种模式与这些药物在毒蕈碱M1受体上的亲和力顺序不一致，而与它们在毒蕈碱M2或M4受体上的亲和力顺序一致。由于震颤性下颌运动与纹状体功能有关，并且毒蕈碱M4受体作为纹状体中的突触后受体比毒蕈碱M2受体更占主导地位，目前的结果表明毛果芸香碱通过刺激毒蕈碱M4受体诱发下颌运动。鉴于帕金森病与拟胆碱药诱发的下颌运动之间的假设关系，这些数据表明一种中枢作用的毒蕈碱M4受体拮抗剂可能作为抗帕金森病药物有用。
