Involvement of 5-HT2A receptor and a2-adrenoceptor blockade in the asenapine-induced elevation of prefrontal cortical monoamine outflow
Involvement of 5-HT2A receptor and a2-adrenoceptor blockade in the asenapine-induced elevation of prefrontal cortical monoamine outflow
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DOI：
10.1002/syn.21551
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发表时间：
2012-07-01
期刊：
影响因子：
2.3
通讯作者：
Svensson, Torgny H.
中科院分区：
文献类型：
--
作者：
Franberg, Olivia;Marcus, Monica M.;Svensson, Torgny H.
精神药物阿塞那平被批准用于治疗精神分裂症和躁狂症或与双相I型障碍相关的混合发作。阿塞那平对几种5-HT受体和a2肾上腺素受体的亲和力高于对D2受体的亲和力。值得注意的是，阻断5-HT2A和a2-肾上腺素能受体可增强D2受体拮抗剂诱导的前额叶多巴胺释放。先前的研究结果表明，阿塞那平可以全身和局部增加内侧前额叶皮层（mPFC）中多巴胺、去甲肾上腺素和血清素的释放，并且多巴胺释放的增加在很大程度上依赖于皮质内作用。通过对自由活动的大鼠进行反向微透析，我们在这里评估了低浓度阿塞那平在体内引起mPFC内5-HT2A受体和a2肾上腺素受体显著的药理学阻塞的效能，从而评估了其影响这些受体释放皮质单胺的能力。皮质内给予1-（2,5-二甲氧基-4-碘苯基）-2-氨基丙烷盐酸盐（DOI）， 5-HT2A/2C受体激动剂，增加皮质单胺释放，阿塞那平和选择性5-HT2A拮抗剂M100907均可拮抗该效应。应用可乐定，一种a2肾上腺素能受体激动剂，显著减少单胺在mPFC中的释放。选择性a2-肾上腺素能受体拮抗剂咪唑嗪阻断，而阿塞那平部分阻断可乐定诱导的皮质多巴胺和去甲肾上腺素的减少。阿塞那平和咪唑嗪对可乐定所致血清素降低的影响不明显。我们的研究结果表明，低浓度的阿塞那平在mPFC中表现出显著的5-HT2A和a2受体拮抗活性，这可能有助于促进体内前额叶单胺的释放，其次，它在精神分裂症和双相情感障碍中的临床效果。突触,2012年。(c) 2012 Wiley期刊有限公司
The psychotropic drug asenapine is approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. Asenapine exhibits higher affinity for several 5-HT receptors and a2-adrenoceptors than for D2 receptors. Noteworthy, blockage of both the 5-HT2A and a2-adrenergic receptors has been shown to enhance prefrontal dopamine release induced by D2 receptor antagonists. Previous results show that asenapine, both systemically and locally, increases dopamine, noradrenaline, and serotonin release in the medial prefrontal cortex (mPFC), and that the increased dopamine release largely depends on an intracortical action. Using reverse microdialysis in freely moving rats, we here assessed the potency of low concentrations of asenapine to cause a pharmacologically significant blockage in vivo of 5-HT2A receptors and a2-adrenoceptors within the mPFC, and thus its ability to affect cortical monoamine release by these receptors. Intracortical administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), a 5-HT2A/2C receptor agonist, increased cortical monoamine release, effects that were antagonized both by asenapine and the selective 5-HT2A antagonist M100907. Application of clonidine, an a2-adrenoceptor agonist, significantly reduced monoamine release in the mPFC. The selective a2-adrenoceptor antagonist idazoxan blocked, whereas asenapine partially blocked clonidine-induced cortical dopamine and noradrenaline decrease. The effects of asenapine and idazoxan on clonidine-induced serotonin decrease were less pronounced. Our results propose that low concentrations of asenapine in the mPFC exhibit a pharmacologically significant 5-HT2A and a2 receptor antagonistic activity, which may contribute to enhance prefrontal monoamine release in vivo and, secondarily, its clinical effects in schizophrenia and bipolar disorder. Synapse, 2012. (c) 2012 Wiley Periodicals, Inc.