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

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).
• 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.