The ability of ketamine administration to activate prefrontal glutamate neurotransmission is thought to be a key mechanism contributing to its transient psychotomimetic effects and its delayed and sustained antidepressant effects. Rodent studies employing carbon-13 magnetic resonance spectroscopy (¹³C MRS) methods have shown ketamine and other N-methyl-D-aspartate (NMDA) receptor antagonists to transiently increase measures reflecting glutamate-glutamine cycling and glutamate neurotransmission in the frontal cortex. However, there are not yet direct measures of glutamate neurotransmission in vivo in humans to support these hypotheses. The current first-level pilot study employed a novel prefrontal ¹³C MRS approach similar to that used in the rodent studies for direct measurement of ketamine effects on glutamate-glutamine cycling. Twenty-one participants (14 healthy and 7 depressed) completed two ¹³C MRS scans during infusion of normal saline or subanesthetic doses of ketamine. Compared to placebo, ketamine increased prefrontal glutamate-glutamine cycling, as indicated by a 13% increase in ¹³C glutamine enrichment (t = 2.4, p = 0.02). We found no evidence of ketamine effects on oxidative energy production, as reflected by ¹³C glutamate enrichment. During ketamine infusion, the ratio of ¹³C glutamate/glutamine enrichments, a putative measure of neurotransmission strength, was correlated with the Clinician-Administered Dissociative States Scale (r = -0.54, p = 0.048). These findings provide the most direct evidence in humans to date that ketamine increases glutamate release in the prefrontal cortex, a mechanism previously linked to schizophrenia pathophysiology and implicated in the induction of rapid antidepressant effects.

中文翻译：

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氯胺酮对健康和抑郁受试者前额叶谷氨酸神经传递的影响。

氯胺酮激活前额叶谷氨酸神经传递的能力被认为是导致其短暂的拟精神病作用及其延迟和持续的抗抑郁作用的关键机制。采用碳 13 磁共振波谱 ( ¹³ C MRS) 方法的啮齿动物研究表明，氯胺酮和其他 N-甲基-D-天冬氨酸 (NMDA) 受体拮抗剂可暂时增加反映额叶皮质中谷氨酸-谷氨酰胺循环和谷氨酸神经传递的测量值。然而，目前还没有直接测量人类体内谷氨酸神经传递的方法来支持这些假设。目前的一级试点研究采用了一种新颖的前额叶¹³ C MRS 方法，类似于啮齿动物研究中使用的方法，用于直接测量氯胺酮对谷氨酸-谷氨酰胺循环的影响。21 名参与者（14 名健康者和 7 名抑郁症患者）在输注生理盐水或亚麻醉剂量的氯胺酮期间完成了两次^{13 C MRS 扫描。与安慰剂相比，氯胺酮增加了前额叶谷氨酸-谷氨酰胺循环， 13} C 谷氨酰胺富集增加了 13% （t = 2.4，p = 0.02）。我们没有发现氯胺酮对氧化能量产生有影响的证据，如¹³ C 谷氨酸富集所反映的那样。^{在氯胺酮输注过程中， 13} C 谷氨酸/谷氨酰胺富集的比率（神经传递强度的推定指标）与临床医生执行的解离状态量表相关（r = -0.54，p = 0.048）。这些发现为人类提供了迄今为止最直接的证据，证明氯胺酮会增加前额皮质中谷氨酸的释放，这一机制以前与精神分裂症的病理生理学有关，并与快速抗抑郁作用的诱导有关。