Iptakalim: a potential antipsychotic drug with novel mechanisms?
Iptakalim: a potential antipsychotic drug with novel mechanisms?
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DOI：
10.1016/j.ejphar.2010.02.024
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发表时间：
2010-05
影响因子：
5
通讯作者：
Tao Sun;Changjiu Zhao;G. Hu;Ming Li
中科院分区：
文献类型：
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作者：
Tao Sun;Changjiu Zhao;G. Hu;Ming Li
Iptakalim是一种新型的三磷酸腺苷（ATP）敏感钾（KATP）通道开启剂。在大脑中，iptakalim被认为作用于神经元和星形细胞质膜和/或线粒体katp通道。由于伊他卡林对前脑区域多巴胺和谷氨酸释放的调节有作用，我们在几个临床前试验中检测了其潜在的抗精神病功效。首先，我们发现伊他卡林在减少安非他明和苯环利定引起的过度运动以及选择性地破坏条件回避反应方面是有效的。接下来，我们发现伊他卡林和安非他明联合治疗可以降低声惊的脉冲前抑制，氟哌啶醇也有这种联合药物作用，但氯氮平没有。最后，我们发现伊他卡林和氯氮平优先增加c-Fos在内侧前额叶皮层、伏隔核和外侧隔核的表达，而氟哌啶醇诱导伏隔核、背外侧纹状体和外侧隔核的表达增加更大。总的来说，我们的研究结果表明，依他卡林可能是一种具有独特作用机制的潜在抗精神病药物。该研究还提示神经元和星形细胞质膜和/或线粒体katp通道可能是抗精神病药物开发中值得关注的新靶点。未来的研究需要使用其他敏感测试来确认iptakalim的这一特性。
Iptakalim is a novel putative adenosine triphosphate (ATP)-sensitive potassium (KATP) channel opener. In the brain, iptakalim is thought to act on the neuronal and astrocytic plasma membrane and/or mitochondrial KATPchannels. Because iptakalim demonstrates an action on the regulation of dopamine and glutamate release in the forebrain regions, we examined its potential antipsychotic efficacy in several preclinical tests. First, we show that iptakalim is effective in reducing amphetamine- and phencyclidine-induced hyperlocomotion as well as selectively disrupting conditioned avoidance responding. Next, we show that combined iptakalim and amphetamine treatment produces a reduction on prepulse inhibition of acoustic startle and this combined drug effect is also found with haloperidol, but not with clozapine. Finally, we show that iptakalim and clozapine preferentially increase c-Fos expression in the medial prefrontal cortex, nucleus accumbens and lateral septal nucleus, whereas haloperidol induces a greater increase in the nucleus accumbens, the dorsolateral striatum and lateral septal nucleus. Collectively, our findings indicate that iptakalim is likely to be a potential antipsychotic drug with distinct mechanisms of action. This study also suggests that neuronal and astrocytic plasma membrane and/or mitochondrial KATPchannels may be a novel target that deserves attention for antipsychotic drug development. Future research using other sensitive tests is needed to confirm this property of iptakalim.