Opposite effects of milnacipran, a serotonin norepinephrine reuptake inhibitor, on the levels of nitric oxide and brain-derived neurotrophic factor in mouse brain cortex

There is a growing body of evidence demonstrating that changes in the brain levels of nitric oxide (NO) and brain-derived neurotrophic factor (BDNF) are implicated in the pathogenesis of major depression. We report here the effects of subchronic treatment of mice with milnacipran, a serotonin norepinephrine reuptake inhibitor, on the levels of NO and BDNF in mice. In vivo administration of milnacipran (10 mg/kg) for 14 days caused a significant decrease in nitrate and nitrite concentrations in the cerebral cortex and hippocampus, but not in the midbrain. Milnacipran (10 mg/kg, 14 days) also decreased the activity of NO synthase in the cerebral cortex. On the other hand, milnacipran (10 mg/kg, 14 days) increased the levels of BDNF protein and mRNA in the cerebral cortex. These findings suggest that milnacipran has opposite effects on the levels of NO and BDNF in the brain cortex, namely, downregulation of NO and upregulation of BDNF.