Effects of Arketamine on Depression-like Behaviors and Demyelination in Mice Exposed to Chronic Restrain Stress: A Role of Transforming Growth Factor-β1

Background: Chronic restrain stress (CRS) induces depression-like behaviors and demyelination in the brain; however, the relationship between these depression-like behaviors and demyelination remains unclear. Arketamine, the (R)-enantiomer of ketamine, has shown rapid antidepressant-like effects in CRS-exposed mice.

Methods: We examined whether arketamine can improve both depression-like behaviors and demyelination in the brains of CRS-exposed mice. Additionally, we investigated the role of transforming growth factor β1 (TGF-β1) in the beneficial effects of arketamine.

Results: A single dose of arketamine (10 mg/kg) improved both depression-like behavior and demyelination in the corpus callosum of CRS-exposed mice. Correlations were found between depression-like behaviors and demyelination in this region. Furthermore, pretreatment with RepSox, an inhibitor of TGF-β1 receptor, significantly blocked the beneficial effects of arketamine on depression-like behaviors and demyelination in CRS-exposed mice. Finally, a single intranasal administration of TGF-β1 ameliorated both depression-like behaviors and demyelination in CRS-exposed mice.

Limitations: The precise mechanisms by which TGF-β1 contributes to the effects of arketamine remain unclear.

Conclusions: These data suggest that CRS-induced demyelination in the corpus callosum may contribute to depression-like behaviors, and that arketamine can mitigate these changes through a TGF-β1-dependent mechanism.