Chaib Sarah, Levigoureux Elise, Bouvard Sandrine, Bouillot Caroline, Vidal Benjamin, Fourier Anthony, Newman-Tancredi Adrian, Zimmer Luc
Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS, INSERM, Lyon, France.
Hospices Civils de Lyon, Lyon, France.
Transl Psychiatry. 2025 Sep 1;15(1):336. doi: 10.1038/s41398-025-03572-4.
Rapid-acting antidepressants (RAADs) such as ketamine are currently under development. The aim of this study is to characterize the neural circuits affected by ketamine and NLX-101, a selective 5-HT receptor biased agonist which has shown promising effects, by using [F]FDG PET imaging in rats that had received chronic administration of corticosterone (CORT), a model of anxiety-depression. In a longitudinal study, regional changes in brain activity were investigated in 24 selected CORT rats. Each animal underwent PET scans in 3 conditions, i.e. with ketamine (10 mg/kg), NLX-101 (0.16 mg/kg) or saline on day 0 and five days later to assess sustained effects. The anxious-depressive phenotype produced by CORT was supported by behavioural and biological observations. Changes in [F]FDG uptake were determined using voxel-based and region of interest analyses. Metabolic connectivity analysis was also performed to investigate the acute and delayed effects of the treatments. Voxel-based and region-of-interest analyses showed marked hypometabolism in regions implicated in depression, particularly cingulate cortex (-7%) and lateral septum (-9%) as well as the striatum (-10%). Acute effects of NLX-101 and ketamine were observed in the lateral septum, resulting in an increase in brain glucose metabolism (p < 0,05). Interestingly, connectivity analyses also showed effects of NLX-101 in the frontal cortex, the thalamus and amygdala (p < 0.05), suggesting that the two molecules converge on common brain regions. This study is the first to show brain activation patterns of RAADs in a CORT rat model by functional PET imaging. NLX-101 appears to exert antidepressant effects by preferentially activating postsynaptic 5-HT heteroreceptors in primary regions common to ketamine. These results support investigation of cortical 5-HT receptors as a target for new generation biased agonist antidepressants.
诸如氯胺酮之类的速效抗抑郁药（RAADs）目前正在研发中。本研究的目的是通过对接受皮质酮（CORT）慢性给药的大鼠（一种焦虑抑郁模型）进行[F]FDG PET成像，来表征受氯胺酮和NLX - 101（一种选择性5 - HT受体偏向激动剂，已显示出有前景的效果）影响的神经回路。在一项纵向研究中，对24只选定的CORT大鼠的脑活动区域变化进行了研究。每只动物在3种条件下接受PET扫描，即在第0天和五天后分别使用氯胺酮（10mg/kg）、NLX - 101（0.16mg/kg）或生理盐水，以评估持续效应。行为和生物学观察结果支持了CORT产生的焦虑抑郁表型。使用基于体素和感兴趣区域分析来确定[F]FDG摄取的变化。还进行了代谢连接性分析以研究治疗的急性和延迟效应。基于体素和感兴趣区域分析显示，与抑郁症相关的区域存在明显的代谢减退，特别是扣带回皮质（-7%）、外侧隔区（-9%）以及纹状体（-10%）。在外侧隔区观察到NLX - 101和氯胺酮的急性效应，导致脑葡萄糖代谢增加（p < 0.05）。有趣的是，连接性分析还显示NLX - 101在额叶皮质、丘脑和杏仁核有作用（p < 0.05），这表明这两种分子在共同的脑区起作用。本研究首次通过功能性PET成像显示了RAADs在CORT大鼠模型中的脑激活模式。NLX - 101似乎通过优先激活氯胺酮共有的主要区域中的突触后5 - HT异源受体来发挥抗抑郁作用。这些结果支持将皮质5 - HT受体作为新一代偏向激动剂抗抑郁药的靶点进行研究。
