LAUSR

Highlightsd‐serine and l‐arginine inhibited the antidepressant‐like effects of GLP‐2 in the mouse FST.PDE5 inhibitor inhibited the antidepressant‐like effects of GLP‐2.GLP‐2 and NMDA receptor‐NO‐cGMP pathway exerted synergistic effects in the FST. &NA; We previously demonstrated that glucagon‐like peptide‐2 (GLP‐2) exerted antidepressant‐like effects in mice. The aim of the present study was to investigate the relationship between N‐methyl‐D‐aspartate (NMDA) receptor‐nitric oxide‐cyclic guanosine monophosphate (NO‐cGMP) pathway and the antidepressant‐like effects of GLP‐2 in the forced‐swim test (FST) in mice. Intracerebroventricularly administered GLP‐2 (3 &mgr;g/mouse) decreased the immobility time in the FST. The pretreatment of mice with l‐arginine (750 mg/kg, i.p.), a substrate for nitric oxide synthase, sildenafil (5 mg/kg, i.p.), a phosphodiesterase 5 inhibitor, or d‐serine (300 mg/kg, i.p.), a NMDA receptor co‐agonist, inhibited the antidepressant‐like effects of GLP‐2 (3 &mgr;g/mouse) in the FST. Meanwhile, l‐nitroarginine methyl ester (10 mg/kg, i.p.), a non‐specific nitric oxide synthase (NOS) inhibitor, 7‐nitroindazole (30 mg/kg, i.p.), a neuronal NOS inhibitor, methylene blue (10 mg/kg, i.p.), an inhibitor of both NOS and soluble guanylate cyclase (sGC), ODQ (30 pmol/site, i.c.v.), a sGC inhibitor, or MK‐801 (0.05 mg/kg, i.p.), an NMDA receptor antagonist, in combination with a sub‐effective dose of GLP‐2 (1.5 &mgr;g/mouse) also decreased the immobility time in the FST. The present study provided evidence for the synergistic antidepressant‐like effects of GLP‐2 and inhibition of the NMDA receptor‐l‐arginine‐NO‐cGMP pathway in the FST, thereby contributing to our understanding of the mechanisms underlying the antidepressant‐like effects of GLP‐2.