The antidepressant action of imipramine and venlafaxine involves suppression of nitric oxide synthesis.

Depressive disorders represent a major public health problem worldwide. The limitations of current antidepressant drugs have warranted on-going research to identify pharmacological agents and strategies that offer a greater therapeutic efficacy. The NMDA/L-arginine nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) cascade is an important signaling pathway that is also implicated in the regulation of depression. In animal models detecting antidepressant activity, distinct NO synthase inhibitors display antidepressant-like action. Therefore, the aim of current study was to evaluate whether pretreatment with L-arginine (precursor of NO) could counteract antidepressant-like effects of distinct antidepressant classes in the mouse forced swimming test (FST), and whether these drugs are able to modulate the nitric oxide synthesis in the brain. We found in the FST that pretreatment with L-arginine (500 mg/kg) counteracted the antidepressant-like effect of imipramine (IMI, 15 mg/kg) and venlafaxine (VENL, 6 mg/kg), but not the effects of bupropion (BUPR, 20mg/kg) or fluoxetine (FLX, 20mg/kg). Increasing the dose of L-Arg to 1000 mg/kg attenuated the antidepressant-like effects of BUPR, but did not modify the action of FLX. L-Arginine was devoid of any locomotor effects on the animals. The effect of antidepressants on brain NO metabolism paralleled their behavioral action in case of IMI and VENL which decreased the nitrite+nitrate concentration in the brain. BUPR and FLX did not have any effect on brain nitrite+nitrate concentration. These results support the idea that some antidepressants are able to inhibit nitric oxide synthesis in the brain, an effect which could be mechanistically related to the ability of L-arginine to counteract their antidepressant-like effects.