The novel antipsychotic drug brexpiprazole, alone and in combination with escitalopram, facilitates prefrontal glutamatergic transmission via a dopamine D1 receptor-dependent mechanism
The novel antipsychotic drug brexpiprazole, alone and in combination with escitalopram, facilitates prefrontal glutamatergic transmission via a dopamine D1 receptor-dependent mechanism
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DOI：
10.1016/j.euroneuro.2017.01.014
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发表时间：
2017-04-01
影响因子：
5.6
通讯作者：
Svensson, Torgny H.
中科院分区：
文献类型：
--
作者：
Bjorkholm, Carl;Marcus, Monica M.;Svensson, Torgny H.
Brexpipazole（Rexulti（R））是一种新型D2/3受体（R）部分激动剂，最近被批准作为精神分裂症的单一疗法，证明了对阳性和阴性症状的有效性，并且还被批准作为抗抑郁药的附加治疗，与单独给予抗抑郁药相比，诱导有效的抗抑郁作用，起效更快。此外，在临床前研究中，布雷哌唑已显示出促认知作用。为了探讨所观察到的效应是否可能通过调节前额叶皮层神经递质传递来介导，我们使用大鼠内侧前额叶皮层（mPFC）深层锥体细胞的体外电生理细胞内记录，研究了布雷哌唑单独使用和与SSRI艾司西酞普兰联合使用对前额叶皮层神经递质传递的影响。纳摩尔浓度的布雷哌唑通过激活多巴胺D1 R增强NMDAR诱导的电流和电诱发的EPSP，与非典型抗精神病药物氯氮平的作用相似。加入艾司西酞普兰后，无效浓度的依哌唑的作用显著增强。当与艾司西酞普兰联合使用时，布雷哌唑也增强了AMPAR介导的传递，与临床上快速起效的抗抑郁药氯胺酮相似。对AMPAR介导的电流的影响也是D1 R依赖性的。总之，我们的数据表明，brexpipazole发挥氯氮平样增强NMDAR介导的电流在mPFC，这可以解释其疗效精神分裂症的阴性症状和临床前观察到的促认知作用。此外，添加依他普仑的布雷哌唑也增强了AMPAR介导的传递，这可能为添加布雷哌唑在重度抑郁症中的更快抗抑郁作用提供了神经生物学解释。(C)2017 Elsevier B.V.和ECNP。All rights reserved.
Brexpiprazole (Rexulti (R)), a novel D2/3 receptor (R) partial agonist, was recently approved as monotherapy for schizophrenia, demonstrating effectiveness against both positive and negative symptoms, and also approved as add-on treatment to antidepressant drugs, inducing a potent antidepressant effect with a faster onset compared to an antidepressant given alone. Moreover, brexpiprazole has demonstrated pro-cognitive effects in preclinical studies. To explore whether the observed effects may be mediated via modulation of prefrontal glutamatergic transmission, we investigated the effect of brexpiprazole, alone and in combination with the SSRI escitalopram, on prefrontal glutamatergic transmission using in vitro electrophysiological intracellular recordings of deep layer pyramidal cells of the rat medial prefrontal cortex (mPFC). Nanomolar concentrations of brexpiprazole potentiated NMDAR-induced currents and electrically evoked EPSPs via activation of dopamine D1Rs, in similarity with the effect of the atypical antipsychotic drug clozapine. The effect of an ineffective concentration of brexpiprazole was significantly potentiated by the addition of escitalopram. When combined with escitalopram, brexpiprazole also potentiated AMPAR-mediated transmission, in similarity with the clinically rapid acting antidepressant drug ketamine. The effect on the AMPAR-mediated currents was also D1R dependent. In conclusion, our data propose that brexpiprazole exerts a clozapine-like potentiation of NMDAR-mediated currents in the mPFC, which can explain its efficacy on negative symptoms of schizophrenia and the pro-cognitive effects observed preclinically. Moreover, add-on brexpiprazole to escitalopram also potentiated AMPAR-mediated transmission, which may provide a neurobiological explanation to the faster antidepressant effect of add-on brexpiprazole in major depression. (C) 2017 Elsevier B.V. and ECNP. All rights reserved.