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開催日 2014/9/11
時間 11:00 - 12:00
会場 Poster / Exhibition(Event Hall B)

Differences in the muscarinic effects of the antipsychotic clozapine and its metabolite N-desmethylclozapine between excitatory and inhibitory hippocampal neurons

  • P1-361
  • 菅原 優翔 / Yuto Sugawara:1 太田 哲生 / Tetsuo Ota:1 少作 隆子 / Takako Ohno-Shosaku:1 
  • 1:金沢大学 / Graduate School of Medical Science, Kanazawa Univ. 

Clozapine is the first atypical antipsychotic, and currently used for treatment-resistant schizophrenic patients. Clozapine and its active metabolite, N-desmethylclozapine (NDMC), exhibit complex pharmacological properties, and interact with various types of receptors for neurotransmitters including dopamine, serotonin, norepinephrine, histamine and acetylcholine. Recent biochemical studies suggested that NDMC exhibits M1 muscarinic agonist action, which is unique and not shared by any other antipsychotics. However, direct electrophysiological evidence for its muscarinic action on intact neurons is poor. Using rat cultured hippocampal neurons, we previously reported that application of a muscarinic agonist, oxotremorine-M (oxo-M), induces suppression of the basal outward K+ current at -40 mV in a PLC-dependent manner. In the present study, using this muscarinic response we examined muscarinic agonist/antagonist properties of NDMC and clozapine in hippocampal excitatory and inhibitory neurons. Pirenzepine (M1 antagonist) antagonized the action of oxo-M more strongly in excitatory neurons than in inhibitory neurons, while DAU5884 (M3 antagonist) tended to suppress the action of oxo-M more strongly in inhibitory neurons than in excitatory neurons, suggesting predominant expression of M1 and M3 receptors in excitatory and inhibitory neurons, respectively. NDMC slightly suppressed the outward K+ current at -40 mV, which was reversed by the muscarinic antagonist atropine. This muscarinic agonist action of NDMC was more prominent in excitatory neurons than in inhibitory ones. In addition, NDMC partially antagonized the action of oxo-M in both excitatory and inhibitory neurons. Compared with NDMC, clozapine exhibited a much weaker agonist action and a stronger antagonist action at muscarinic receptors. These results strongly suggest that NDMC acts as a partial M1 agonist and M1/M3 antagonist, whereas clozapine acts as a potent M1/M3 antagonist.

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