کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
4323544 1613800 2016 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Electrophysiological evidence showing muscarinic agonist–antagonist activities of N-desmethylclozapine using hippocampal excitatory and inhibitory neurons
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی علوم اعصاب (عمومی)
پیش نمایش صفحه اول مقاله
Electrophysiological evidence showing muscarinic agonist–antagonist activities of N-desmethylclozapine using hippocampal excitatory and inhibitory neurons
چکیده انگلیسی


• Antipsychotic clozapine and its metabolite (NDMC) were applied to hippocampal cells.
• NDMC, but not clozapine, suppressed K+channels via M1 receptors in excitatory cells.
• This M1 agonist activity of NDMC was partially masked when co-applied with clozapine.

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 M1 muscarinic receptors. However, direct electrophysiological evidence showing the ability of NDMC to activate native M1 receptors 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 M1 antagonist pirenzepine was evident only in excitatory neurons, while the M3 antagonist 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 M1 receptors 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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Brain Research - Volume 1642, 1 July 2016, Pages 255–262
نویسندگان
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