title: Guanosine produces an antidepressant-like effect through the modulation of NMDA receptors, nitric oxide-cGMP and PI3K/mTOR pathways.
abstract: 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 (0.5-5 mg/kg) and TST (0.05-0.5 mg/kg). The anti-immobility effect of guanosine in the TST was prevented by the treatment of mice with NMDA (0.1 pmol/site, i.c.v.), d-serine (30 μg/site, i.c.v., a co-agonist of NMDA receptors), l-arginine (750 mg/kg, i.p., a substrate for nitric oxide synthase), sildenafil (5 mg/kg, i.p., a phosphodiesterase 5 inhibitor), LY294002 (10 μg/site, i.c.v., a reversible PI3K inhibitor), wortmannin (0.1 μg/site, i.c.v., an irreversible PI3K inhibitor) or rapamycin (0.2 nmol/site, i.c.v., a selective mTOR inhibitor). In addition, the administration of ketamine (0.1 mg/kg, i.p., a NMDA receptor antagonist), MK-801 (0.001 mg/kg, i.p., another NMDA receptor antagonist), 7-nitroindazole (50 mg/kg, i.p., a neuronal nitric oxide synthase inhibitor) or ODQ (30 pmol/site i.c.v., a soluble guanylate cyclase inhibitor) in combination with a sub-effective dose of guanosine (0.01 mg/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.
authors: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900, Florianópolis, SC, Brazil.
authors: Luis E B
authors: LE
authors: Bettio
authors: Mauricio P
authors: MP
authors: Cunha
authors: Josiane
authors: J
authors: Budni
authors: Francis L
authors: FL
authors: Pazini
authors: Ágatha
authors: Á
authors: Oliveira
authors: André R
authors: AR
authors: Colla
authors: Ana Lúcia S
authors: AL
authors: Rodrigues
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001120:Arginine / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D006151:Guanosine / Q000494:pharmacology / Q000627:therapeutic use*; D019417:Hindlimb Suspension / Q000523:psychology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012694:Serine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D013550:Swimming / Q000523:psychology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D001120:Arginine; D006152:Cyclic GMP; D004791:Enzyme Inhibitors; D018683:Excitatory Amino Acid Agents; D006151:Guanosine; D007166:Immunosuppressive Agents; D016202:N-Methylaspartate; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases