Gigout S, Wierschke S, Dehnicke C, Deisz R A
Centre for Anatomy, Institute for Cell Biology and Neurobiology, Charité Universitätsmedizin Berlin, Philippstrasse, 12, 10115, Berlin, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2015 May;388(5):487-96. doi: 10.1007/s00210-014-1080-3. Epub 2015 Jan 16.
Cholinergic transmission plays a pivotal role in learning, memory and cognition, and disturbances of cholinergic transmission have been implicated in neurological disorders including Alzheimer's disease, epilepsy and schizophrenia. Pharmacological alleviation of these diseases by drugs including N-desmethylclozapine (NDMC), promising in animal models, often fails in patients. We therefore compared the effects of NDMC on glutamatergic and GABAergic transmission in slices from rat and human neocortex. We used carbachol (CCh; an established agonist at metabotropic muscarinic acetylcholine (ACh) receptors (mAChRs)) as a reference. Standard electrophysiological methods including intracellular and field potential recordings were used. In the rat neocortex, NDMC prevented the CCh-induced decrease of GABAA and GABAB receptor-mediated responses but not the CCh-induced increase of the paired-pulse depression. NDMC reduced neither the amplitude of the excitatory postsynaptic potentials (EPSP) nor antagonized the CCh-induced depression of EPSP. In the human neocortex, however, NDMC failed to prevent CCh-induced decrease of the GABAB responses and directly reduced the amplitude of EPSP. These data suggest distinct effects of NDMC in rat and human at M2 and M4 mAChRs underlying presynaptic modulation of GABA and glutamate release, respectively. In particular, NDMC might be a M2 mAChR antagonist in the rat but has no activity at this receptor in human neocortex. However, NDMC has an agonistic effect at M4 mAChR in the human but no such effect in the rat neocortex. The present study confirms that pharmacology at mAChRs can differ between species and emphasizes the need of studies in human tissue.
胆碱能传递在学习、记忆和认知中起关键作用，胆碱能传递紊乱与包括阿尔茨海默病、癫痫和精神分裂症在内的神经疾病有关。包括N-去甲基氯氮平（NDMC）在内的药物在动物模型中显示出对这些疾病有药理学缓解作用，但在患者中往往无效。因此，我们比较了NDMC对大鼠和人类新皮质切片中谷氨酸能和γ-氨基丁酸能传递的影响。我们使用卡巴胆碱（CCh；一种已确定的代谢型毒蕈碱型乙酰胆碱（ACh）受体（mAChRs）激动剂）作为对照。采用了包括细胞内和场电位记录在内的标准电生理方法。在大鼠新皮质中，NDMC可防止CCh诱导的GABAA和GABAB受体介导反应的降低，但不能防止CCh诱导的双脉冲抑制增加。NDMC既不降低兴奋性突触后电位（EPSP）的幅度，也不拮抗CCh诱导的EPSP抑制。然而，在人类新皮质中，NDMC未能防止CCh诱导的GABAB反应降低，并直接降低了EPSP的幅度。这些数据表明，NDMC在大鼠和人类中对分别位于GABA和谷氨酸释放突触前调节基础上的M2和M4 mAChRs有不同的作用。特别是，NDMC在大鼠中可能是一种M2 mAChR拮抗剂，但在人类新皮质中对该受体无活性。然而，NDMC在人类中对M4 mAChR有激动作用，而在大鼠新皮质中无此作用。本研究证实了mAChRs的药理学在不同物种之间可能存在差异，并强调了在人体组织中进行研究的必要性。
