ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Neuropharmacology
Time-Dependent Biphasic Alterations in Brain Metabolism Following Chronic Ketamine Exposure in Mice
Provisionally accepted
- Graduate School, Yonsei University, Seoul, Republic of Korea
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Background: Ketamine has attracted clinical interest for its therapeutic potential, but prolonged exposure raises concerns about dependence and its long-term effects on brain metabolism. Materials and Methods: Male mice received daily intraperitoneal injections of ketamine (30 mg/kg) for 28 days. Brain glucose metabolism was evaluated using [18F]FDG positron emission tomography (PET) at 1 hour, 1 week, and 1 month post-injection. Expression levels of glucose transporters (GLUT1), glycolytic enzymes (PKM2, HK1), NMDA receptor subunits (NR2B), and apoptotic markers (caspase-3) were analyzed by Western blotting and RT-PCR. Results: FDG-PET imaging suggested a biphasic metabolic pattern, with an increase in uptake at 1 hour and 1 week, followed by a significant reduction by 1 month, returning toward baseline levels. GLUT1 mRNA expression gradually increased, although protein levels did not show a clear parallel change. PKM2 and HK1 remained largely unchanged. At 1 month, NR2B and caspase-3 transcripts were elevated, while protein-level changes were less evident, suggesting possible transcriptional regulation of stress-related pathways. Discussion: These findings demonstrate that ketamine induces dynamic alterations in brain glucose metabolism accompanied by molecular adaptations. The early hypermetabolic response may reflect acute excitatory effects, whereas longer exposure could engage compensatory or stress-associated mechanisms. Metabolic imaging may provide a useful, non-invasive approach to better understand ketamine’s temporal effects and support long-term safety monitoring.
Keywords: Ketamine, FDG-PET, brain metabolism, GLUT1, chronic exposure
Received: 16 May 2025; Accepted: 27 Oct 2025.
Copyright: © 2025 Lim, Choi, Kim, Kim and Song. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ho Taek Song, hotsong@yuhs.ac
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