The Comparative Sensitivity to Ketamine-Induced Neuronal Death in Juvenile and Adult Rats.
Sumit Sarkar, Gonçalo Gamboa da Costa, Kellie Woodling, Shiny Mathew, Ikram Elayan, John Talpos
International journal of toxicology June 4, 2026 DOI: 10.1177/10915818261455819 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Juvenile and adult rats |
| Intervention | Ketamine |
| Dose | 50, 75, and 100 mg/kg |
| Duration | 72 hours post-treatment |
| Topics | Esketamine Ketamine |
| Keywords | Mk-801 Nmda receptor Adolescence Age Neurotoxicity Pharmacokinetics Sex differences |
| Key findings | Acute ketamine (100 mg/kg) caused neuronal necrosis in the retrosplenial cortex of adult female rats but not in juvenile rats or adult males, with elevated norketamine levels in adult females potentially contributing to the effect. |
Abstract
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, was first approved by the US FDA as KETALAR® for induction and maintenance of general anesthesia. Ketamine has been used off-label for depression treatment, while its S-enantiomer, esketamine (SPRAVATO®), is approved for treatment-resistant depression and major depressive disorder with acute suicidal ideation or behavior. High doses of ketamine have been linked to neurotoxicity. The effects of acute ketamine exposure on brain development during childhood and adolescence in humans remain poorly understood. To better characterize the safety of ketamine, we treated juvenile (postnatal day (PND) 21, 30, 35) and adult rats (PND 90) with a single subcutaneous dose of ketamine (50, 75, and 100 mg/kg). Seventy-two hours later, tissue samples were collected. Tissue samples were processed, mounted as 5-µm-thick sections, and stained with H&E for neurohistopathological evaluation. Additionally, key pharmacokinetic parameters of ketamine were determined. Neuronal necrosis was detected in the retrosplenial cortex in adult female rats treated with ketamine (100 mg/kg), while no histological changes were observed in any other groups. These data are the first to demonstrate that acute ketamine can cause neuronal necrosis in adult animals and do not support juvenile rats as having an increased susceptibility to ketamine-induced neuronal death. Adult female rats showed a marked increase in norketamine, the primary metabolite of ketamine in serum. We hypothesize that the elevated levels of norketamine may contribute to these sex- and age-specific histopathological changes.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 6
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- NMDA Antagonist Neurotoxicity: Mechanism and Prevention Science December 6, 1991
- Sex Differences in the Pharmacokinetics of Low-dose Ketamine in Plasma and Brain of Male and Female Rats. Journal of Pharmacology and Experimental Therapeutics December 2018
- Antidepressant-like effects of ketamine, norketamine and dehydronorketamine in forced swim test: Role of activity at NMDA receptor. Neuropharmacology December 1, 2015
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