Pharmacological evidence for the relationship between the NMDA receptor and nitric oxide pathway and the antidepressant-like effects of glucagon-like peptide-2 in the mouse forced-swim test.

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 μg/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 μg/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 μg/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.