Recent studies highlight the involvement of the nitrergic system in the mechanism of action of antidepressant drugs. Sildenafil, a selective PDE5 inhibitor, was shown to abolish the anti-immobility effects of bupropion, venlafaxine and s-citalopram in mice. In this study we assessed the effects of sildenafil on the activity of bupropion and venlafaxine in the forced swim test in mice. Swim trials were conducted by placing mice in glass cylinders filled with water for 6min and the duration of the behavioral immobility during the last 4min of the test was evaluated. Locomotor activity was evaluated with photoresistor actimeters. Brain and serum concentrations of the studied antidepressants were determined by HPLC method. Sildenafil at a dose of 20mg/kg, but not 5 and 10mg/kg, significantly increased the anti-immobility action of bupropion (20mg/kg). The antidepressant activity of venlafaxine (2mg/kg) was potentiated by joint administration with sildenafil at doses of 10 and 20mg/kg. Since the combined treatments did not increase the locomotor activity, the antidepressant-like effects were not related to non-specific behavioral activation. Data from pharmacokinetic studies revealed that sildenafil increased bupropion and venlafaxine levels in serum without affecting their concentrations in the brain. The present study demonstrates the enhancement of anti-immobility action of bupropion and venlafaxine by sildenafil co-administration. The observed changes might have been partly due to pharmacokinetic interactions. However, mechanisms underlying the effects of sildenafil on the antidepressant activity of bupropion and venlafaxine should be carefully evaluated in further studies.
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