CB1R-dependent mitochondrial biogenesis may contribute to the antidepressant effects of esketamine in a chronic variable stress male mouse model.

Major depressive disorder (MDD) is a leading cause of disability worldwide, and current antidepressants are limited by delayed onset and incomplete efficacy. Esketamine produces antidepressant effects more rapidly than conventional treatments, but its underlying mechanisms remain unclear. We examined whether cannabinoid type 1 receptor (CB1R) signaling is associated with hippocampal mitochondrial biogenesis-related changes following esketamine treatment in a chronic variable stress (CVS) mouse model. Mice underwent 21 days of CVS and received a single intraperitoneal injection of esketamine (15 mg/kg) 24 h before behavioral testing. Hippocampal CB1R, nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), and total cytochrome C expression were assessed by Western blotting. Additional groups received the CB1R antagonists AM251 or SR141716A before esketamine administration. CVS induced depressive-like behavioral changes in the forced swim, tail suspension, and novelty-suppressed feeding tests. These effects were accompanied by reduced hippocampal CB1R, NRF1, and TFAM expression and altered total cytochrome c expression. Esketamine reversed the behavioral abnormalities and normalized these molecular changes. Pretreatment with either CB1R antagonist prevented both the behavioral and molecular effects of esketamine. These findings indicate that the antidepressant-like effects of esketamine observed 24 h after administration are associated with CB1R-dependent changes in hippocampal mitochondrial biogenesis-related protein expression. Further studies using direct mitochondrial functional assays and loss-of-function approaches are needed to establish causality.