ENANTIOMER-SPECIFIC EFFECTS OF SUBANESTHETIC KETAMINE ON FRONTAL CORTICAL GLUCOSE METABOLISM IN HEALTHY RAT BRAIN

Major depressive disorder (MDD) is a highly prevalent affective disorder, with approximately one-third of patients failing to respond to conventional antidepressant treatments. Ketamine, an N-methyl-D-aspartate receptor (NMDA-R) antagonist, produces rapid antidepressant effects at subanaesthetic doses and represents a promising therapeutic option for treatment-resistant depression (TRD). Ketamine is a racemic mixture of S-ketamine and R-ketamine. Racemic ketamine and S‑ketamine have demonstrated clinical efficacy in TRD, and R‑ketamine has shown antidepressant‑like effects in preclinical models, however, the neurobiological mechanisms underlying their enantiomer‑specific actions remain poorly understood. Alterations in cerebral glucose metabolism have been reported in MDD, and changes in metabolic activity have been associated with symptom improvement following antidepressant treatment. The aim of this study was to compare the acute effects of S-ketamine and R-ketamine on cerebral glucose metabolism. Regional brain glucose metabolism was assessed in healthy female Sprague–Dawley rats using [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography at baseline and one hour after the administration of either S-ketamine or R-ketamine. S-ketamine induced significant increases in glucose metabolism relative to baseline in the medial prefrontal cortex, frontal association cortex, and orbitofrontal cortex, regions implicated in mood regulation and cognitive processing. In contrast, R-ketamine produced no detectable changes relative to baseline. These findings demonstrate distinct enantiomer-specific effects of ketamine on brain glucose metabolism and provide insight into neural mechanisms that may contribute to their differential therapeutic profiles in affective disorders.