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Nitric oxide, a secondary messenger molecule, has been implicated in neurotransmission, synaptic plasticity, learning, aggression and depression. <jats:italic>Vaccinium myrtillus<\/jats:italic> (bilberry) extract is a potent inhibitor of reactive oxygen\/nitrogen species and cytokine production. The present study investigated the role of nitric oxide in the antidepressant action of <jats:italic>Vaccinium myrtillus<\/jats:italic> in unpredictable chronic mild stress\u2010induced depression in mice. Animals were subjected to different stress paradigms daily for a period of 21\u2009days to induce depressive\u2010like behavior. Pretreatment with <jats:sc>l<\/jats:sc>\u2010arginine significantly reversed the protective effect of bilberry (500\u2009mg\/kg) on chronic stress\u2010induced behavioral (immobility period, sucrose preference) and biochemical (lipid peroxidation and nitrite levels; endogenous antioxidant activities) in stressed mice. Furthermore, <jats:sc>l<\/jats:sc>\u2010NAME (10\u2009mg\/kg) pretreatment with a sub\u2010effective dose of bilberry (250\u2009mg\/kg) significantly potentiated the protective effect of bilberry extract. The study revealed that modulation of the nitric oxide pathway might be involved in antidepressant\u2010like effects of <jats:italic>Vaccinium myrtillus<\/jats:italic> in stressed mice. 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