Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects.
Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects.
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DOI：
10.1038/mp.2016.34
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发表时间：
2017-01
影响因子：
11
通讯作者：
Sanacora G
中科院分区：
文献类型：
--
作者：
Chowdhury GM;Zhang J;Thomas M;Banasr M;Ma X;Pittman B;Bristow L;Schaeffer E;Duman RS;Rothman DL;Behar KL;Sanacora G
最近有报道称，在临床试验和啮齿动物模型中，有几种药物可以产生快速的抗抑郁效果。尽管所涉及的细胞机制尚不清楚，但报告表明，谷氨酸传递的增加有助于这些影响。在这里，我们证明了三种独特的药物的抗抑郁类疗效，据报道具有快速起效的抗抑郁特性，与清醒大鼠内侧额前皮质(MPFC)谷氨酸循环的快速瞬时增加相结合，这是通过体外1H-[13C]-核磁共振波谱测量的。用氯胺酮(1，3，10，30，80 mg/kg)、RO25-6981(1，3，10 mg/kg)、东莨菪碱(5，25,100μg/kg)或赋形剂(对照组)进行急性预处理。在注射药物后的固定时间，动物静脉输注[1，6-13C2]葡萄糖8min，用13C丰富脑内氨基酸池，然后快速安乐死。分离mPFC，乙醇提取，测定代谢产物~(13)C浓缩率。我们发现氯胺酮和RO25-6981对小鼠的行为和谷氨酸、谷氨酰胺和GABA的~(13)C浓集百分率有明显的剂量依赖关系。此外，我们还发现东莨菪碱对骑车和行为都有影响。这些研究表明，三类药理上不同的药物，通过其快速的抗抑郁作用在临床上相关，具有共同的能力，以与其抗抑郁药类似的疗效相关的剂量快速刺激谷氨酸循环。我们得出结论，在行为有效剂量下，循环次数增加先于抗抑郁作用，提示循环次数的快速变化可用于预测新药的疗效或识别具有抗抑郁活性的剂量。
Several drugs have recently been reported to induce rapid antidepressant effects in clinical trials and rodent models. Although the cellular mechanisms involved remain unclear, reports suggest that increased glutamate transmission contributes to these effects. Here, we demonstrate that the antidepressant-like efficacy of three unique drugs, with reported rapid onset antidepressant properties, is coupled with a rapid transient rise in glutamate cycling in medial prefronal cortex (mPFC) of awake rats as measured by ex vivo 1H-[13C]-nuclear magnetic resonance spectroscopy. Rats were acutely pre-treated by intraperitoneal injection with a single dose of ketamine (1,3,10,30,80mg/kg), Ro 25-6981 (1,3,10mg/kg), scopolamine (5,25,100μg/kg) or vehicle (controls). At fixed times after drug injection animals received an intravenous infusion of [1,6-13C2]glucose for 8 min to enrich brain amino acid pools with 13C, followed by rapid euthanasia. The mPFC was dissected, extracted with ethanol and metabolite 13C enrichments measured. We found a clear dose dependent effect of ketamine and Ro 25-6981 on behavior and the percent of 13C-enrichment of glutamate, glutamine and GABA. Further, we also found an effect of scopolamine on both cycling and behavior. These studies demonstrate that three pharmacologically distinct classes of drugs, clinically related through their reported rapid antidepressant actions, share the common ability to rapidly stimulate glutamate cycling at doses pertinent for their antidepressant-like efficacy. We conclude that increased cycling precedes the antidepressant action at behaviorally effective doses and suggests the rapid change in cycling could be used to predict efficacy of novel agents or identify doses with antidepressant activity.