Stress-induced excessive glutamate transmission at N-methyl-D-aspartate receptors (NMDA-R’s) may underlie a primary mechanism in the physiology that leads to depression, and ketamine, an NMDA-R antagonist, has been shown to rapidly relieve depression in humans. A number of downstream mechanisms have been suggested to mediate the antidepressant action of ketamine, including the activation of extracellular-signal-regulated kinases 1/2 (ERK1/2), protein kinase B (or Akt) and the mammalian target of rapamycin (mTOR). However, the mechanism(s) that are affected immediately downstream of NMDA-R’s remain unclear. Neuronal nitric oxide synthase (nNOS) is directly coupled to and activated by NMDA-R’s, and the uncoupling of the nNOS-NMDA-R complex prevents NMDA-R-mediated excitotoxicity. Therefore, we investigated whether the antidepressant mechanism of ketamine involves the inhibition of nitric oxide (NO) signalling. We used a genetic rat model of depression, the Flinders Sensitive Line (FSL) rats, and their control, the Flinders Resistant Line (FRL) rats, to investigate whether l-arginine, a precursor of NO, can attenuate the behavioural antidepressant-like effect of ketamine in FSL rats in the forced swim test (FST), and whether l-arginine can prevent the phosphorylation of ERK1/2, Akt and mTOR by ketamine in the frontal cortex in these rats. We also measured the activity of nNOS activity in this region. Four groups of FSL rats received vehicle (saline, i.p.), ketamine (15 mg/kg, i.p.), l-arginine (250 mg/kg, i.p.) or a combination of ketamine and l-arginine, and assessed in the FST 1 hour later, whereafter their brains were dissected for subsequent western blotting and nNOS activity assays. One vehicle-treated group of FRL rats was used to validate the model. Behavioural results showed that l-arginine significantly attenuated the antidepressant-like action of ketamine in the FST, indicating that ketamine may exert its antidepressant action by reducing NO signalling. Western blotting and nNOS activity experiments are on going and these results are imminent.