Background and Aim: Stress-induced excessive glutamate transmission at N-methyl-D-aspartate (NMDA) receptors may underlie a major mechanism in the pathophysiology that leads to depression, while ketamine, an NMDA receptor antagonist, has been shown to induce a rapid antidepressant effect in depressed patients following a single intravenous administration that is sustained for ± 7 days. A number of downstream cellular mechanisms appear to mediate the antidepressant action of ketamine, and the majority of evidence point to a rapid activation of protein translation leading to increased synaptic protein synthesis in the frontal cortex as vital processes that underlie its antidepressant action. However, the upstream mechanism(s) that are affected, i.e. immediately downstream of NMDA receptors, remain unclear. Neuronal nitric oxide synthase (nNOS) is directly coupled to and activated by NMDA receptors, while the uncoupling of the nNOS-NMDA receptor complex prevents NMDA-induced excitotoxicity. Thus, it is possible that the inhibition of nitric oxide (NO) signalling underlies a key upstream mechanism in the antidepressant action of ketamine. Methods: We used a genetic rat model of depression, the Flinders Sensitive Line (FSL) rats, which present with increased depression-like behaviour and abnormalities in NO signalling and synaptic protein regulation, compared to their control, the Flinders Resistant Line (FRL) rats to test our hypothesis. Specifically, we investigated whether l-arginine, a precursor and a stimulant of NO production can attenuate behavioural and cellular antidepressant-like effects induced by ketamine. 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 the frontal cortex regions were dissected for the measurement of nNOS activity and synaptic proteins (i.e. GluR1, GluR2, NR2A/B, NR1 and PSD-95) using western blotting. A vehicle-treated group of FRL rats was included as behavioural validation and to characterise the FSL/FRL model in more detail with regard to the regulation of these proteins. Results: The behavioural data from the FST showed that l-arginine significantly attenuated the antidepressant-like action of ketamine, suggesting that ketamine may indeed exert its antidepressant action by reducing NO signalling. However, molecular experiments that may shed more light on this mechanism are currently in progress and we expect these results to be available soon.