Lamotrigine is an anticonvulsant agent that shows clinical antidepressant properties. The aim of the present study was to investigate the involvement of N-methyl-d-aspartate (NMDA) receptors and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) synthesis in possible antidepressant-like effect of lamotrigine in forced swimming test (FST) in mice. Intraperitoneal administration of lamotrigine (10 mg/kg) decreased the immobility time in the FST (P < 0.01) without any effect on locomotor activity in the open-field test (OFT), while higher dose of lamotrigine (30 mg/kg) reduced the immobility time in the FST (P < 0.001) as well as the number of crossings in the OFT. Pretreatment of animals with NMDA (75 mg/kg), l-arginine (750 mg/kg, a substrate for nitric oxide synthase [NOS]) or sildenafil (5 mg/kg, a phosphodiesterase [PDE] 5 inhibitor) reversed the antidepressant-like effect of lamotrigine (10 mg/kg) in the FST. Injection of l-nitroarginine methyl ester (l-NAME, 10 mg/kg, a non-specific NOS inhibitor), 7-nitroindazole (30 mg/kg, a neuronal NOS inhibitor), methylene blue (20 mg/kg, an inhibitor of both NOS and soluble guanylate cyclase [sGC]), or MK-801 (0.05 mg/kg), ketamine (1 mg/kg), and magnesium sulfate (10 mg/kg) as NMDA receptor antagonists in combination with a sub-effective dose of lamotrigine (5 mg/kg) diminished the immobility time of animals in the FST compared with either drug alone. None of the drugs produced significant effects on the locomotor activity in the OFT. Based on our findings, it is suggested that the antidepressant-like effect of lamotrigine might mediated through inhibition of either NMDA receptors or NO-cGMP synthesis.