Smolders I, Bogaert L, Ebinger G, Michotte Y
Department of Pharmaceutical Chemistry and Drug Analysis, Vrije Universiteit Brussel, Belgium.
J Neurochem. 1997 May;68(5):1942-8. doi: 10.1046/j.1471-4159.1997.68051942.x.
Intrastriatal microdialysis was used to administer muscarinic drugs in freely moving rats for 40 min at a flow rate of 2 microl/min. Administration of the nonselective agonist pilocarpine at 10 mM increased striatal dopamine release and decreased extracellular GABA and glutamate overflow. Perfusion with the muscarinic M2 antagonist methoctramine at 75 microM increased extracellular dopamine and glutamate concentrations but exerted no changes on extracellular GABA levels. Intrastriatal administration of the M1 antagonist pirenzepine at 0.05 microM decreased extracellular dopamine overflow. Application of pirenzepine (0.05 and 5 microM) exerted no effects on the measured GABA or glutamate levels. There are thus important differences in applied doses of muscarinic drugs needed to obtain modulatory effects. High doses of agonists are probably needed to superimpose on the background of tonic influences of striatal acetylcholine, whereas antagonists can block the receptors in small doses. We further suggest that M1 receptors might tonically facilitate striatal dopamine release, that M2 receptors might tonically inhibit striatal glutamate efflux, and that acetylcholine does not exert tonic effects on striatal GABA release. The link with the pilocarpine animal model for temporal lobe epilepsy will be discussed.
在自由活动的大鼠中，采用纹状体内微透析技术，以2微升/分钟的流速给予毒蕈碱药物40分钟。给予10毫摩尔/升的非选择性激动剂毛果芸香碱可增加纹状体多巴胺释放，并降低细胞外γ-氨基丁酸（GABA）和谷氨酸溢出。用75微摩尔/升的毒蕈碱M2拮抗剂美索曲明灌注可增加细胞外多巴胺和谷氨酸浓度，但对细胞外GABA水平无影响。纹状体内给予0.05微摩尔/升的M1拮抗剂哌仑西平可降低细胞外多巴胺溢出。应用哌仑西平（0.05和5微摩尔/升）对所测GABA或谷氨酸水平无影响。因此，获得调节作用所需的毒蕈碱药物应用剂量存在重要差异。可能需要高剂量的激动剂来叠加纹状体乙酰胆碱的紧张性影响背景，而拮抗剂小剂量即可阻断受体。我们进一步认为，M1受体可能紧张性促进纹状体多巴胺释放，M2受体可能紧张性抑制纹状体谷氨酸外流，且乙酰胆碱对纹状体GABA释放无紧张性作用。将讨论与颞叶癫痫的毛果芸香碱动物模型的联系。
