Research reportAttenuation of oxidative and nitrosative stress in cortical area associates with antidepressant-like effects of tropisetron in male mice following social isolation stress

- Adolescence SIS provoked depressive-like behaviors in socially isolated male mice.
- SIS induced mitochondrial dysfunction and O&NS stress in the cortical areas.
- Tropisetron attenuated the negative effect of SIS on behavioral tests.
- Tropisetron reversed mitochondrial dysfunction and O&NS stress of cortex.
- Nitrergic system is partially involved in protective effects of tropisetron.

Tropisetron, a 5-HT3 receptor antagonist widely used as an antiemetic, has been reported to have positive effects on mood disorders. Adolescence is a critical period during the development of brain, where exposure to chronic stress during this time is highly associated with the development of depression. In this study, we showed that 4 weeks of juvenile social isolation stress (SIS) provoked depressive-like behaviors in male mice, which was associated with disruption of mitochondrial function and nitric oxide overproduction in the cortical areas. In this study, tropisetron (5 mg/kg) reversed the negative behavioral effects of SIS in male mice. We found that the effects of tropisetron were mediated through mitigating the negative activity of inducible nitric oxide synthase (iNOS) on mitochondrial activity. Administration of aminoguanidine (specific iNOS inhibitor, 20 mg/kg) augmented the protective effects of tropisetron (1 mg/kg) on SIS. Furthermore, l-arginine (nitric oxide precursor, 100 mg/kg) abolished the positive effects of tropisetron. These results have increased our knowledge on the pivotal role of mitochondrial function in the pathophysiology of depression, and highlighted the role of 5-HT3 receptors in psychosocial stress response during adolescence. Finally, we observed that tropisetron alleviated the mitochondrial dysfunction through decreased nitrergic system activity in the cerebral cortex.