Electrophysiological evidence showing muscarinic agonist-antagonist activities of N-desmethylclozapine using hippocampal excitatory and inhibitory neurons.
Electrophysiological evidence showing muscarinic agonist-antagonist activities of N-desmethylclozapine using hippocampal excitatory and inhibitory neurons.
复制标题
电生理学证据显示 N-去甲基氯氮平对海马兴奋性和抑制性神经元具有毒蕈碱激动剂-拮抗剂活性。
DOI：
10.1016/j.brainres.2016.03.054
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发表时间：
2016
期刊：
影响因子：
2.9
通讯作者：
Ohno-Shosaku T
中科院分区：
文献类型：
--
作者：
Sugawara Y;Kikuchi Y;Yoneda M;Ohno-Shosaku T
非典型抗精神病药氯氮平被广泛用于难治性精神分裂症患者。氯氮平及其主要活性代谢物N-去甲基氯氮平（NDMC）具有复杂的药理学性质，并与多种神经递质受体相互作用。有几项生化研究报告，NDMC对人重组M1毒蕈碱受体表现出部分激动剂特征。然而，直接的电生理证据表明，NDMC激活天然M1受体在完整的神经元的能力是穷人。使用大鼠海马神经元，我们先前证明了毒蕈碱受体被毒蕈碱激动剂oxotremorine M（oxo-M）激活后，在−40 mV下诱导外向K+电流减少。在本研究中，使用这种毒蕈碱电流反应，我们评估了激动剂和拮抗剂活性的氯氮平和NDMC在本地毒蕈碱受体在完整的海马兴奋性和抑制性神经元。M1拮抗剂哌仑西平仅在兴奋性神经元中抑制oxo-M诱导的电流反应，而M3拮抗剂达非那新在两种类型的神经元中均有效。NDMC的毒蕈碱激动剂活性高于氯氮平，兴奋性神经元高于抑制性神经元，对哌仑西平敏感，与氯氮平合用时部分被掩蔽。氯氮平和NDMC的M受体拮抗活性在兴奋性和抑制性神经元之间无差异，但氯氮平的作用强于NDMC。这些结果表明，NDMC有能力激活海马兴奋性神经元中表达的天然M1受体，但其激动剂活性可能是有限的氯氮平治疗的患者，因为过量的氯氮平与毒蕈碱拮抗剂活性的存在。
The atypical antipsychotic clozapine is widely used for treatment-resistant schizophrenic patients. Clozapine and its major active metabolite,N-desmethylclozapine (NDMC), have complex pharmacological properties, and interact with various neurotransmitter receptors. There are several biochemical studies reporting that NDMC exhibits a partial agonist profile at the human recombinant M1muscarinic receptors. However, direct electrophysiological evidence showing the ability of NDMC to activate native M1receptors in intact neurons is poor. Using rat hippocampal neurons, we previously demonstrated that activation of muscarinic receptors by a muscarinic agonist, oxotremorine M (oxo-M), induces a decrease in outward K+current at −40 mV. In the present study, using this muscarinic current response we assessed agonist and antagonist activities of clozapine and NDMC at native muscarinic receptors in intact hippocampal excitatory and inhibitory neurons. Suppression of the oxo-M-induced current response by the M1antagonist pirenzepine was evident only in excitatory neurons, while the M3antagonist darifenacin was effective in both types of neurons. Muscarinic agonist activity of NDMC was higher than that of clozapine, higher in excitatory neurons than in inhibitory neurons, sensitive to pirenzepine, and partially masked when co-applied with clozapine. Muscarinic antagonist activity of clozapine as well as NDMC was not different between excitatory and inhibitory neurons, but clozapine was more effective than NDMC. These results demonstrate that NDMC has the ability to activate native M1receptors expressed in hippocampal excitatory neurons, but its agonist activity might be limited in clozapine-treated patients because of the presence of excessive clozapine with muscarinic antagonist activity.