Huntington's disease (HD), a basal ganglia disorder, is characterized not only by a spectrum of motor deficits, but also by emotional, cognitive and psychiatric manifestations. Cognitive impairment is one of the serious manifestations of this disease in the later stage of life. Although there is currently no cure for HD, there has been a surge of clinical trials involving patients with HD over the past 5 years. However, cognitive measures have generally been lacking from these trials. The beneficial effect of antidepressants in HD has been suggested in recent clinical trials. However, their mechanism of action is still not clear. Therefore, this study was designed to elucidate and compare the mechanistic role of different classes of antidepressants (sertraline, venlafaxine, imipramine and trazodone) against 3-nitropropionic acid (3-NP)-induced cognitive impairment, oxidative stress (glutathione) and mitochondrial dysfunction in rat hippocampus. Systemic treatment with 3-NP (10 mg/kg for 14 days) significantly impaired memory performance (both in the Morris water maze and elevated plus maze escape retention test), oxidative defence (glutathione redox status) and mitochondrial enzyme complex activities in rat hippocampus. Sertraline, venlafaxine, imipramine and trazodone treatments significantly improved performance in both cognitive tasks and glutathione redox status, and restored mitochondrial enzyme complex activities, as compared with the 3-NP treated group. L-arginine (50 mg/kg) pretreatment for 14 days together with a subeffective dose of sertraline (10 mg/kg), venlafaxine (10 mg/kg), imipramine (10 mg/kg) or trazodone (10 mg/kg) partially attenuated their protective effects. Further, G-nitro-L-Arginine-Methyl Ester (10 mg/kg) pretreatment together with subeffective dose of sertraline (10 mg/kg), venlafaxine (10 mg/kg), imipramine (10 mg/kg) and trazodone (10 mg/kg) significantly enhanced their efficacy. The results of this study suggest that nitric oxide modulation is involved in their protective effect of antidepressants against 3-NP induced cognitive dysfunction in rats.