Erb C, Troost J, Kopf S, Schmitt U, Löffelholz K, Soreq H, Klein J
Department of Pharmacology, University of Mainz, Mainz, Germany.
J Neurochem. 2001 Apr;77(2):638-46. doi: 10.1046/j.1471-4159.2001.00287.x.
Central cholinergic neurotransmission was studied in learning-impaired transgenic mice expressing human acetylcholinesterase (hAChE-Tg). Total catalytic activity of AChE was approximately twofold higher in synaptosomes from hippocampus, striatum and cortex of hAChE-Tg mice as compared with controls (FVB/N mice). Extracellular acetylcholine (ACh) levels in the hippocampus, monitored by microdialysis in the absence or presence of 10(-8)-10(-3) M neostigmine in the perfusion fluid, were indistinguishable in freely moving control and hAChE-Tg mice. Muscarinic receptor functions were unchanged as indicated by similar effects of scopolamine on ACh release and of carbachol on inositol phosphate formation. However, when the mice were anaesthetized with halothane (0.8 vol. %), hippocampal ACh reached significantly lower levels in AChE-Tg mice as compared with controls. Also, the high-affinity choline uptake (HACU) in hippocampal synaptosomes from awake hAChE-Tg mice was accelerated but was reduced by halothane anaesthesia. Moreover, hAChE-Tg mice displayed increased motor activity in novel but not in familiar environment and presented reduced anxiety in the elevated plus-maze test. Systemic application of a low dose of physostigmine (100 microgram/kg i.p.) normalized all of the enhanced parameters in hAChE-Tg mice: spontaneous motor activity, hippocampal ACh efflux and hippocampal HACU, attributing these parameters to the hypocholinergic state due to excessive AChE activity. We conclude that, in hAChE-Tg mice, hippocampal ACh release is up-regulated in response to external stimuli thereby facilitating cholinergic neurotransmission. Such compensatory phenomena most likely play important roles in counteracting functional deficits in mammals with central cholinergic dysfunctions.
在表达人乙酰胆碱酯酶（hAChE-Tg）的学习障碍转基因小鼠中研究了中枢胆碱能神经传递。与对照组（FVB/N小鼠）相比，hAChE-Tg小鼠海马、纹状体和皮质突触体中AChE的总催化活性高约两倍。在灌注液中不存在或存在10(-8)-10(-3)M新斯的明的情况下，通过微透析监测自由活动的对照小鼠和hAChE-Tg小鼠海马中的细胞外乙酰胆碱（ACh）水平没有差异。东莨菪碱对ACh释放的影响以及卡巴胆碱对肌醇磷酸形成的影响相似，表明毒蕈碱受体功能未改变。然而，当用氟烷（0.8体积%）麻醉小鼠时，与对照组相比，hAChE-Tg小鼠海马中的ACh水平显著降低。此外，清醒的hAChE-Tg小鼠海马突触体中的高亲和力胆碱摄取（HACU）加快，但氟烷麻醉使其降低。此外，hAChE-Tg小鼠在新环境中表现出运动活动增加，但在熟悉环境中没有，并且在高架十字迷宫试验中表现出焦虑减轻。全身应用低剂量毒扁豆碱（100微克/千克腹腔注射）使hAChE-Tg小鼠的所有增强参数恢复正常：自发运动活动、海马ACh外流和海马HACU，将这些参数归因于由于AChE活性过高导致的胆碱能功能减退状态。我们得出结论，在hAChE-Tg小鼠中，海马ACh释放因外部刺激而上调，从而促进胆碱能神经传递。这种代偿现象很可能在抵消中枢胆碱能功能障碍的哺乳动物的功能缺陷中起重要作用。
