Atypical antipsychotic drug olanzapine inhibits 5-HT3 receptor-mediated currents by allosteric and non-competitive mechanisms

• 발행기관: 대한생리학회-대한약리학회
• 저자명: Yong Soo Park Gyu Min Kim Ho Jun Sung Ju Yeong Yu Ki-Wug Sung
• 간행물 정보: 『The Korean Journal of Physiology & Pharmacology』제29권 제4호, 431~442쪽, 전체 12쪽
• 주제분류: 의약학 > 의학일반
• 파일형태: PDF
• 발행일자: 2025.06.30

국문 초록

Olanzapine, an atypical antipsychotic, is widely used in the treatment of schizophrenia and bipolar disorder due to its modulation of dopamine and serotonin receptor systems. While its primary action involves antagonism of dopamine D2 and serotonin 5-HT (5-hydroxytryptamine)2A receptors, recent evidence suggests that olanzapine also inhibits 5-HT3 receptors, which are ligand-gated ion channels involved in synaptic transmission in central and peripheral nervous systems. The present study aimed to investigate the action of olanzapine on 5-HT3 receptor-mediated currents using whole-cell voltage-clamp recordings in NCB-20 neuroblastoma cells. Results of this study indicated that olanzapine could act as a non-competitive antagonist of the 5-HT3 receptor, exhibiting concentration-dependent inhibition of ion currents. Moreover, olanzapine facilitated both deactivation and desensitization kinetics, accelerating decay of 5-HT3 receptor-mediated currents. Recovery from desensitization was significantly delayed by olanzapine, whereas recovery from deactivation was largely unaffected by it. Current-voltage relationship analysis revealed that olanzapine reduced the amplitude of 5-HT3 receptor-mediated currents across all holding potentials without altering reversal potential, suggesting a voltage-independent inhibition. Furthermore, olanzapine exhibited use-dependent inhibition, with a greater reduction in current observed during more frequent 5-HT application. These findings provide novel insights into a non-competitive and allosteric inhibition of 5-HT3 receptors by olanzapine, contributing to a deeper understanding of its pharmacological profile in neuropsychiatric and gastrointestinal conditions where serotonergic neurotransmission is implicated.

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키워드

Allosteric regulation Olanzapine Patch-clamp techniques Schizophrenia 5-HT3 receptor