Guanosine produces an antidepressant-like effect through the modulation of NMDA receptors, nitric oxide–cGMP and PI3K/mTOR pathways

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Guanosine is an extracellular signaling molecule implicated in the modulation of glutamatergic transmission and neuroprotection. The present study evaluated the antidepressant-like effect of guanosine in the forced swimming test (FST) and in the tail suspension test (TST) in mice. The contribution of NMDA receptors as well as l-arginine–NO–cGMP and PI3K–mTOR pathways to this effect was also investigated. Guanosine administered orally produced an antidepressant-like effect in the FST (0.5–5mg/kg) and TST (0.05–0.5mg/kg). The anti-immobility effect of guanosine in the TST was prevented by the treatment of mice with NMDA (0.1pmol/site, i.c.v.), d-serine (30μg/site, i.c.v., a co-agonist of NMDA receptors), l-arginine (750mg/kg, i.p., a substrate for nitric oxide synthase), sildenafil (5mg/kg, i.p., a phosphodiesterase 5 inhibitor), LY294002 (10μg/site, i.c.v., a reversible PI3K inhibitor), wortmannin (0.1μg/site, i.c.v., an irreversible PI3K inhibitor) or rapamycin (0.2nmol/site, i.c.v., a selective mTOR inhibitor). In addition, the administration of ketamine (0.1mg/kg, i.p., a NMDA receptor antagonist), MK-801 (0.001mg/kg, i.p., another NMDA receptor antagonist), 7-nitroindazole (50mg/kg, i.p., a neuronal nitric oxide synthase inhibitor) or ODQ (30pmol/site i.c.v., a soluble guanylate cyclase inhibitor) in combination with a sub-effective dose of guanosine (0.01mg/kg, p.o.) reduced the immobility time in the TST when compared with either drug alone. None of the treatments affected locomotor activity. Altogether, results firstly indicate that guanosine exerts an antidepressant-like effect that seems to be mediated through an interaction with NMDA receptors, l-arginine–NO–cGMP and PI3K–mTOR pathways.