Effect of D-cycloserine in conjunction with fear extinction training on extracellular signal-regulated kinase activation in the medial prefrontal cortex and amygdala in rat.
Effect of D-cycloserine in conjunction with fear extinction training on extracellular signal-regulated kinase activation in the medial prefrontal cortex and amygdala in rat.
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DOI：
10.1111/ejn.12197
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发表时间：
2013-06
期刊：
影响因子：
--
通讯作者：
Dravid SM
中科院分区：
文献类型：
--
作者：
Gupta SC;Hillman BG;Prakash A;Ugale RR;Stairs DJ;Dravid SM
D-环丝氨酸（DCS）目前正在进行一些神经精神疾病的临床试验，并已被发现可以增强啮齿动物的恐惧消退和人类的暴露疗法。然而，DCS在这些多种模式中作用的分子机制仍不清楚。在这里，我们描述了DCS管理的影响，单独或与灭绝训练，神经元活性（c-fos）和神经元可塑性（磷酸化细胞外信号调节激酶，pERK）标记，使用免疫组织化学。我们发现，在未经训练的年轻大鼠（24-28日龄）的DCS腹腔注射增加c-fos和pERK染色的神经元在内侧前额叶皮层（mPFC）的边缘前（PL）和边缘下（IL）分区和中央杏仁核（CeA）的外侧核（CeL）的pERK水平降低。此外，DCS管理显着增加GluA 1，GluN 1，GluN 2A，和GluN 2B在mPFC的表达。在另一组动物中，我们发现与盐水对照相比，DCS促进了恐惧消退，并增加了IL，PL，闰间细胞和CeL中的pERK水平。在synaptoneurosomal准备，我们发现，灭绝训练增加iGluR蛋白的表达mPFC，上下文动物相比。在mPFC中，在预防生理盐水和预防DCS组之间未观察到蛋白质表达的显著差异。与此相反，在杏仁核DCS与灭绝训练导致iGluR亚基的表达增加，相比，抑制生理盐水组。我们的数据表明，DCS在神经精神疾病中的疗效可能部分是由于其能够影响mPFC和杏仁核亚核中的神经元活动和信号传导。
D-cycloserine (DCS) is currently under clinical trials for a number of neuropsychiatric conditions and has been found to augment fear extinction in rodents and exposure therapy in humans. However, the molecular mechanism of DCS action in these multiple modalities remains unclear. Here, we describe the effect of DCS administration, alone or in conjunction with extinction training, on neuronal activity (c-fos) and neuronal plasticity (phospho-extracellular signal-regulated kinase, pERK) markers using immunohistochemistry. We found that intraperitoneal administration of DCS in untrained young rats (24–28 days old) increased c-fos and pERK-stained neurons in both the prelimbic (PL) and infralimbic (IL) division of the medial prefrontal cortex (mPFC) and reduced pERK levels in the lateral nucleus (CeL) of the central amygdala (CeA). Moreover, DCS administration significantly increased GluA1, GluN1, GluN2A, and GluN2B expression in mPFC. In a separate set of animals, we found that DCS facilitated fear extinction and increased pERK levels in IL, PL, intercalated cells and CeL, compared to saline control. In synaptoneurosomal preparation, we found that extinction training increased iGluR protein expression in the mPFC, compared to context animals. No significant difference in protein expression was observed between extinction-saline and extinction-DCS groups in the mPFC. In contrast, in the amygdala DCS in conjunction with extinction training led to an increase in iGluR subunit expression, compared to extinction-saline group. Our data suggest that the efficacy of DCS in neuropsychiatric disorders may be partly due to its ability to affect neuronal activity and signaling in the mPFC and amygdala subnuclei.
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