Ketamine, an NMDA receptor antagonist and fast acting antidepressant, produces a rapid burst of glutamate in the ventral medial prefrontal cortex (mPFC). Preclinical studies have demonstrated that pyramidal cell activity in the vmPFC is necessary for the rapid antidepressant response to ketamine in rodents. We sought to characterize the effects of ketamine and its stereoisomers (R and S), as well as a metabolite, (2R,6R)-hydroxynorketamine (HNK), on vmPFC activity using a genetically encoded calcium indicator (GCaMP6f). Ratiometric fiber photometry was utilized to monitor GCaMP6f fluorescence in pyramidal cells of mouse vmPFC prior to and immediately following administration of compounds. GCaMP6f signal was assessed to determine correspondance of activity between compounds. We observed dose dependent effects with (R,S)-ketamine (3-100 mg/kg), with the greatest effects on GCaMP6f activity at 30 mg/kg and lasting up to 20 min. (S)-ketamine (15 mg/kg), which has high affinity for the NMDA receptor channel produced similar effects to (R,S)-ketamine, but compounds with low NMDA receptor affinity, including (R)-ketamine (15 mg/kg) and (2R,6R)-HNK (30 mg/kg) had little or no effect on GCaMP6f activity. The initial response to administration of (R,S)-ketamine as well as (S)-ketamine is characterized by a brief period of robust GCaMP6f activation, consistent with increased activity of vmPFC pyramidal neurons. Because (2R,6R)-HNK and (R)-ketamine are reported to have antidepressant activity in rodent models the current results indicate that different initiating mechanisms lead to similar brain adaptive consequences that underlie the rapid antidepressant responses.

中文翻译：

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氯胺酮增加vmPFC活性：（R）-和（S）-立体异构体以及（2R，6R）-羟基降氯胺酮代谢产物的作用。

氯胺酮是NMDA受体拮抗剂和速效抗抑郁药，可在腹内侧前额叶皮层（mPFC）中快速产生谷氨酸。临床前研究表明，vmPFC中的锥体细胞活性对于啮齿动物对氯胺酮的快速抗抑郁反应是必需的。我们试图使用基因编码的钙指示剂（GCaMP6f）表征氯胺酮及其立体异构体（R和S）以及代谢产物（2R，6R）-羟基降甲胺酮（HNK）对vmPFC活性的影响。在施用化合物之前和之后，利用比例纤维光度法监测小鼠vmPFC锥体细胞中GCaMP6f的荧光。评估GCaMP6f信号以确定化合物之间活性的对应关系。我们观察到（R，S）-氯胺酮（3-100 mg / kg）的剂量依赖性效应，在30 mg / kg的条件下对GCaMP6f活性的影响最大，持续时间长达20分钟。对NMDA受体通道具有高亲和力的（S）-氯胺酮（15 mg / kg）与（R，S）-氯胺酮产生相似的作用，但NMDA受体亲和力低的化合物包括（R）-氯胺酮（15 mg / kg） / kg）和（2R，6R）-HNK（30 mg / kg）对GCaMP6f活性影响很小或没有影响。给予（R，S）-氯胺酮和（S）-氯胺酮的初始反应的特征是短暂的稳健GCaMP6f激活，这与vmPFC锥体神经元活性的增加相一致。因为据报道（2R，6R）-HNK和（R）-氯胺酮在啮齿动物模型中具有抗抑郁活性，所以目前的结果表明，不同的启动机制会导致类似的大脑适应性后果，这些后果是快速抗抑郁反应的基础。