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 Peer reviewed DOI: 10.1177/10915818261455819 via PubMed
Summary
Acute ketamine exposure can cause neuronal necrosis in adult female rats at a dose of 100 mg/kg, but juvenile rats do not show increased susceptibility to this effect. In the study, no histological changes were observed in juvenile rats treated with doses of 50, 75, or 100 mg/kg. Additionally, adult females exhibited higher levels of norketamine, the primary metabolite of ketamine, which may relate to the observed neurotoxic effects.
Study at a glance
| Design | experimental study |
|---|---|
| Population | juvenile and adult rats |
| Key finding | Neuronal necrosis was detected in the retrosplenial cortex of adult female rats treated with ketamine at a dose of 100 mg/kg. |
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.