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The Comparative Sensitivity to Ketamine-Induced Neuronal Death in Juvenile and Adult Rats.

Sumit Sarkar1, Gonçalo Gamboa da Costa1, Kellie Woodling1

  • 1U.S. Food & Drug Administration, National Center for Toxicological Research, U.S. FDA, Jefferson, AR, USA.

International Journal of Toxicology
|June 4, 2026
PubMed
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Acute ketamine exposure caused neuronal necrosis in adult female rats, not juveniles. Elevated norketamine levels may explain these sex- and age-specific effects, suggesting caution with ketamine use.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Toxicology

Background:

  • Ketamine, an NMDA receptor antagonist, is approved for anesthesia and off-label for depression.
  • Esketamine, its S-enantiomer, is approved for treatment-resistant depression and suicidal ideation.
  • High-dose ketamine is linked to neurotoxicity, but effects on developing brains are unclear.

Purpose of the Study:

  • To investigate the neurohistopathological effects of acute ketamine exposure in juvenile and adult rats.
  • To determine if juvenile rats exhibit increased susceptibility to ketamine-induced neurotoxicity.
  • To characterize ketamine pharmacokinetics and identify potential sex- and age-specific differences.

Main Methods:

  • Juvenile (PND 21, 30, 35) and adult (PND 90) rats received a single subcutaneous ketamine dose (50-100 mg/kg).
Keywords:
MK-801NMDA receptoradolescenceageneurotoxicitypharmacokineticssex differences

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  • Neurohistopathological evaluation using H&E staining was performed on brain tissue 72 hours post-administration.
  • Ketamine and norketamine serum levels were determined to assess pharmacokinetic parameters.

    • Main Results:

    • Neuronal necrosis was observed in the retrosplenial cortex of adult female rats receiving 100 mg/kg ketamine.
    • No histological changes were detected in juvenile rats or other adult groups.
    • Adult female rats exhibited significantly higher serum norketamine levels, the primary ketamine metabolite.

    Conclusions:

    • Acute ketamine administration can induce neuronal necrosis in adult rats, specifically in adult females.
    • Juvenile rats do not show increased susceptibility to ketamine-induced neuronal death compared to adults.
    • Elevated norketamine levels in adult female rats may underlie the observed sex- and age-specific neurotoxic effects.