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

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.