Converging evidence has shown that acute administration of ketamine in a sub-anaesthetic dose exerts fast-acting and robust antidepressant properties in patients suffering from major depressive disorder.However,the underlying mechanisms have not been fully elucidated.The present study aimed to investigate the role of the L-arginine-nitric oxide pathway in the antidepressant effects of ketamine on rats in the forced swimming test (FST).Ketamine 10 mg/kg significantly decreased the immobility time in the FST and the activities of total nitric oxide synthases (T-NOS),inducible NOS (iNOS),and endothelial NOS (eNOS) in the rat hippocampus.Interestingly,the plasma activities of T-NOS,iNOS,and eNOS increased after the ketamine administration.Furthermore,the activities of neuronal NOS (nNOS) displayed no significant change in either the hippocampus or plasma after the ketamine administration.The antidepressant effects of ketamine were prevented by L-arginine 750 mg/kg pretreatment.The pretreatment with a NOS inhibitor L-NG-nitroarginine methyl ester,at a sub-antidepressant dose of 50 mg/kg,and ketamine at a sub-antidepressant does of 3 mg/kg reduced the immobility time in the FST when compared with either drug alone.None of the drugs affected the scores of crossing and rearings in the open field test.The results suggest that the L-arginine-nitric oxide pathway is deeply involved in the antidepressant effects of ketamine on rats in the FST,which is characterized by the the inhibition of brain T-NOS,iNOS,and eNOS activities.