Chaib Sarah, Bouillot Caroline, Bouvard Sandrine, Vidal Benjamin, Zimmer Luc, Levigoureux Elise
Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS, INSERM, Lyon, France.
Hospices Civils de Lyon, Lyon, France.
Front Neurosci. 2023 Jul 13;17:1213941. doi: 10.3389/fnins.2023.1213941. eCollection 2023.
Ketamine, a glutamate NMDA receptor antagonist, is suggested to act very rapidly and durably on the depressive symptoms including treatment-resistant patients but its mechanisms of action remain unclear. There is a requirement for non-invasive biomarkers, such as imaging techniques, which hold promise in monitoring and elucidating its therapeutic impact.
We explored the glucose metabolism with [F]FDG positron emission tomography (PET) in ten male rats in a longitudinal study designed to compare imaging patterns immediately after acute subanaesthetic ketamine injection (i.p. 10 mg/kg) with its sustained effects, 5 days later. Changes in [F]FDG uptake following ketamine administration were estimated using a voxel-based analysis with SPM12 software, and a region of interest (ROI) analysis. A metabolic connectivity analysis was also conducted to estimate the immediate and delayed effects of ketamine on the inter-individual metabolic covariance between the ROIs.
No significant difference was observed in brain glucose metabolism immediately following acute subanaesthetic ketamine injection. However, a significant decrease of glucose uptake appeared 5 days later, reflecting a sustained and delayed effect of ketamine in the frontal and the cingulate cortex. An increase in the raphe, caudate and cerebellum was also measured. Moreover, metabolic connectivity analyses revealed a significant decrease between the hippocampus and the thalamus at day 5 compared to the baseline.
This study showed that the differences in metabolic profiles appeared belatedly, 5 days after ketamine administration, particularly in the cortical regions. Finally, this methodology will help to characterize the effects of future molecules for the treatment of treatment resistant depression.
氯胺酮是一种谷氨酸N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，被认为能非常迅速且持久地作用于包括难治性患者在内的抑郁症状，但其作用机制仍不清楚。需要非侵入性生物标志物，如成像技术，有望用于监测和阐明其治疗效果。
我们在一项纵向研究中，用[F]氟代脱氧葡萄糖正电子发射断层扫描（PET）对10只雄性大鼠的葡萄糖代谢进行了探索，该研究旨在比较急性亚麻醉剂量氯胺酮腹腔注射（10mg/kg）后即刻及其5天后的持续效应的成像模式。使用SPM12软件基于体素的分析和感兴趣区域（ROI）分析来估计氯胺酮给药后[F]氟代脱氧葡萄糖摄取的变化。还进行了代谢连接性分析，以估计氯胺酮对ROI之间个体间代谢协方差的即刻和延迟效应。
急性亚麻醉剂量氯胺酮注射后即刻，脑葡萄糖代谢未观察到显著差异。然而，5天后葡萄糖摄取出现显著下降，反映了氯胺酮在额叶和扣带回皮质的持续和延迟效应。中缝核、尾状核和小脑也有增加。此外，代谢连接性分析显示，与基线相比，第5天时海马体和丘脑之间有显著下降。
本研究表明，代谢特征差异在氯胺酮给药5天后才出现，特别是在皮质区域。最后，这种方法将有助于表征未来治疗难治性抑郁症分子的效果。
