Evidence for the involvement of L-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of memantine in mice

This study investigated the involvement of the L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in the antidepressant-like effect of an acute administration of memantine in the forced swimming test (FST) in mice, since this signaling pathway is supposed to play a significant role in depression. The antidepressant-like effect of memantine (3 mg/kg, i.p.) was prevented by pretreatment with L-arginine (750 mg/kg, i.p.) or S-nitroso-N-acetyl-penicillamine (SNAP, 25 mu g/site, i.c.v.), but not with D-arginine (750 mg/kg, i.p.). The treatment of mice with N-nitro-L-arginine (L-NNA, 0.03 and 0.3 mg/kg, i.p.) potentiated the effect of a subeffective dose of memantine (0.3 mg/kg, i.p.) in the FST. Moreover, the pretreatment of mice with (1H-[1,2,4]oxadiazole[4,3-alquinoxalin-1-one) (ODQ, 30pmol/site, i.c.v.) produced a synergistic antidepressant-like effect with subeffective doses of memantine (0.3 and 1 mg/kg, i.p.) in the FST. Furthermore, the reduction in the immobility time elicited by memantine (3 mg/kg, i.p.) in the FST was prevented by pretreatment with sildenafil (5 mg/kg, i.p.). Taken together, the results demonstrate that memantine produced an anti depressant-like effect in the FST that seems to be mediated through an interaction with the L-arginine-NO-cGMP pathway. (c) 2005 Elsevier B.V. All rights reserved.