Role of the nitric oxide donor sodium nitroprusside in the antidepressant effect of ketamine in mice

Ketamine may represent an efficient alternative antidepressant with rapid therapeutic onset; however, the clinical use of ketamine is hampered by psychosis-like side-effects. Recent studies suggest that the nitric oxide (NO) donor sodium nitroprusside (SNP) prevents psychosis-like abnormalities triggered by ketamine or another NMDA receptor (NMDAR) antagonist, phencyclidine (PCP) in rats. SNP was shown to elicit antipsychotic effects also in humans. Considering the tight interrelation between NMDAR activation and neuronal NO synthesis, we evaluated the effect of pre-treatment with SNP on the antidepressant action of ketamine. We found that SNP (0.5-1 mg/kg, i.p.) did not alter the antidepressant effect of ketamine (30 mg/kg) in the Porsolt Forced Swim Test (FST) in mice. Additionally, SNP by itself produced no effect in the FST or in the openfield. This suggests indirectly a differential involvement of the nitrinergic system in the antidepressant vs. psychotomimetic effect of ketamine, although an influence of species-specific differences cannot be excluded in this interpretation.