Inhibition of the TNF-α/IDO1 Axis Restores Brain Serotonin and Mitigates Aggression-like Phenotypes in BCG-inoculated Mice

Aggression is linked to systemic inflammation and serotonergic dysfunction. Tumor necrosis factor-alpha (TNF-α), a key pro-inflammatory cytokine, disrupts serotonin synthesis by upregulating indoleamine 2,3-dioxygenase 1 (IDO1), which diverts tryptophan metabolism away from serotonin production. This study investigated whether inhibiting the TNF-α/IDO1 signaling pathway could reduce aggressive behavior. Aggression-like behaviors were induced in mice using Bacillus Calmette–Guérin (BCG), known to elevate systemic TNF-α and reduce brain serotonin. Behavioral assessments included the Social Aggression Test (SAT), Rod Biting Test (RBT), and locomotor activity. Biochemical analyses of TNF-α (plasma and amygdala) and serotonin (amygdala) were conducted using ELISA and HPLC. Treatment groups received either the TNF-α inhibitor etanercept, the IDO1 inhibitor minocycline, or both. BCG-inoculated mice exhibited increased aggression and reduced serotonin levels, alongside elevated TNF-α in the amygdala. Etanercept significantly reduced aggressive behavior and restored serotonin levels. Co-treatment with minocycline further enhanced these effects. Locomotor activity remained unchanged across all groups. TNF-α inhibition mitigates aggression by restoring serotonin levels, likely through suppression of IDO1 activity. Co-inhibition of IDO1 enhances this effect, highlighting the TNF-α/IDO1 pathway as a promising target for managing aggression.