At sub-anaesthetic doses, ketamine, a non competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated remarkable and rapid antidepressant (AD) efficacy in patients with treatment-resistant depression (TRD). However, its mechanism of action of ketamine is not fully understood. Since comorbid depression and anxiety disorders often occur, GABAergic/inhibitory and glutamatergic/excitatory drug treatments may be co-administered in these patients. Information regarding this combination is critical to establish efficacy or treatment restrictions to maximize translation from animal models to TRD patients, effectiveness and safety. To assess the specific role of excitatory/inhibitory neurotransmission in the medial prefrontal cortex-raphe nuclei (mPFC-DRN) circuit in the sustained antidepressant-like activity (AD) of ketamine (at t24h post dose), AMPA-R antagonist (intra-DRN) and GABA_A-R agonist (intra-mPFC) were co-administered with ketamine (intra-mPFC). Twenty-four hours later, responses in the forced swim test (FST) and neurochemical consequences on extracellular mPFC glutamate, GABA and 5-HT levels were measured in BALB/cJ mice. Intra-DRN NBQX prevented the sustained AD-like activity of ketamine evidenced by decreases in FST swimming duration and blunted cortical 5-HT_ext and Glu_ext. Intra-mPFC muscimol blocked ketamine AD-like activity and its effects on cortical 5-HT_ext. Moreover, a selective glutamate transporter GLT-1 inhibitor, dihydrokainic acid (DHK) locally perfused into the mPFC produced an AD-like activity at t24h associated with robust increases in mPFC 5-HT_ext, Glu_ext and GABA_ext. Thus, the sustained AD-like activity of ketamine is triggered by AMPA-R activation in the DRN and 5-HT - glutamate release in the mPFC, but limited by GABA_A-R activation - GABA release in the mPFC. The local blockade of GLT-1 in the mPFC also mimics the rapid responses of ketamine, thus highlighting the role of neuronal-glial adaptation in these effects. These results also suggests the need to test for the concomitant prescription of ketamine and BZD to see whether its sustained antidepressant activity is maintained in TRD patients.

在亚麻醉剂量下，氯胺酮是一种非竞争性的N-甲基-d-天冬氨酸（NMDA）受体拮抗剂已显示出对患有抗药性抑郁症（TRD）的患者具有显着且快速的抗抑郁（AD）功效。但是，氯胺酮的作用机理尚未完全了解。由于经常发生合并抑郁症和焦虑症，因此这些患者可以联合使用GABA能/抑制性和谷氨酸能/兴奋性药物治疗。有关此组合的信息对于建立疗效或治疗限制，以最大程度地从动物模型翻译为TRD患者，有效性和安全性至关重要。评估兴奋性/抑制性神经传递在内侧前额叶皮层-raphe核（mPFC-DRN）回路中在氯胺酮（给药后t24h）的持续抗抑郁样活性（AD），AMPA-R拮抗剂（内- DRN）和GABA_甲-R激动剂（帧内的mPFC）共施用氯胺酮（帧内的mPFC）。24小时后，在BALB / cJ小鼠中测量了强迫游泳试验（FST）的反应以及对细胞外mPFC谷氨酸，GABA和5-HT水平的神经化学后果。DRN内NBQX阻止了氯胺酮的持续AD样活性，这可通过FST游泳时间的减少和皮质5-HT _ext和Glu _ext钝化来证明_。内-mPFC muscimol阻断氯胺酮AD样活性及其对皮质5-HT _ext的影响。此外，局部灌注到mPFC中的选择性谷氨酸转运蛋白GLT-1抑制剂二氢海藻酸（DHK）在t24h产生了AD样活性，与mPFC 5-HT _ext，Glu _ext的强劲增加有关。和GABA _ext。因此，氯胺酮的持续AD样活性由DRN中的AMPA-R激活和mPFC中的5-HT-谷氨酸释放触发，但受GABA _A -R激活-mPFC中的GABA释放限制。在mPFC中对GLT-1的局部阻滞也模仿了氯胺酮的快速反应，从而突显了神经胶质适应在这些作用中的作用。这些结果还表明需要测试氯胺酮和BZD的并用处方，以查看TRD患者是否维持其持续的抗抑郁活性。