Single dose S-ketamine rescues transcriptional dysregulation of Mtor and Nrp2 in the prefrontal cortex of FSL rats 1hour but not 14 days post dosing.
Betina Elfving, Nico Liebenberg, Kristian Du Jardin, C. Sánchez, Gregers Wegener, H. Müller
European Neuropsychopharmacology November 11, 2022 DOI: 10.1016/j.euroneuro.2022.10.011 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL) rats |
| Intervention | S-ketamine |
| Dose | 15 mg/kg |
| Duration | Assessments at 1 hour, 2 days, and 14 days after a single dose |
| Topics | Esketamine Ketamine |
| Key findings | S-ketamine (15 mg/kg) produced rapid (1 hour) and sustained (2 and 14 days) antidepressant-like effects in FSL rats. FSL rats showed transcriptional evidence of suppressed VEGF signaling compared with FRL rats, and S-ketamine's transcriptional effects occurred mainly in the acute phase, including restoration of reduced Nrp2 and Mtor in FSL prefrontal cortex. |
Abstract
There is a pressing need to identify biological indicators of major depression to help guide proper diagnosis and optimize treatment. Animal models mimicking aspects of depression constitute essential tools for early-stage exploration of relevant pathways. In this study, we used the Flinders Sensitive and Resistant Line (FSL/FRL) to explore central and peripheral transcriptional changes in vascular endothelial growth factor (VEGF) pathway genes and their temporal regulation after a single dose of S-ketamine (15 mg/kg). We found that S-ketamine induced both rapid (1 hour) and sustained (2 and 14 days) antidepressant-like effects in the FSL rats. Analysis of mRNA expression revealed significant strain effects of Vegf, Vegf164, Vegfr-1, Nrp1, Nrp2, Rictor, and Raptor in the prefrontal cortex (PFC) and of Vegf164, GbetaL, and Tsc1 in the hippocampus (HIP), which indicates suppression of VEGF signaling in the FSL rats compared to FRL rats. This notion was further substantiated by reduced expression of Vegf and Mtor in plasma from FSL rats. In the brain, S-ketamine induced transcriptional changes in the acute phase, not the sustained phase. There were significant treatment effects of S-ketamine on Vegfr-2 in both PFC and HIP and on Vegf and Vegfr-1 in HIP. Moreover, we found that S-ketamine specifically restored reduced levels of Nrp2 and Mtor in the PFC of the FSL rats. In conclusion, this study substantiates the use of the FRL/FSL rats to explore the depressive-like behavior at the transcriptional level of the VEGF pathway genes and study their regulation in response to various treatment paradigms.
Comparable studies
Other preclinical and animal studies on esketamine, most cited first.
Citations in the library
Cited by 2
- Shared effects of electroconvulsive shocks and ketamine on neuroplasticity: A systematic review of animal models of depression. Neuroscience & Biobehavioral Reviews September 1, 2024
- Esketamine alleviates the pain-depression dyad: insights from exploratory transcriptomic profiling and Wnt4-associated molecular alterations within the anterior cingulate cortex Frontiers in Pharmacology October 16, 2026
Cites 5
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Role of Neuronal VEGF Signaling in the Prefrontal Cortex in the Rapid Antidepressant Effects of Ketamine American Journal of Psychiatry January 4, 2019
- S-Ketamine Mediates Its Acute and Sustained Antidepressant-Like Activity through a 5-HT1B Receptor Dependent Mechanism in a Genetic Rat Model of Depression Frontiers in Pharmacology January 15, 2018
- Nitric oxide involvement in the antidepressant-like effect of ketamine in the Flinders sensitive line rat model of depression Acta Neuropsychiatrica April 1, 2015
- NMDA Receptor Blockade at Rest Triggers Rapid Behavioural Antidepressant Responses Nature June 15, 2011