title: The modulation of NMDA receptors and L-arginine/nitric oxide pathway is implicated in the anti-immobility effect of creatine in the tail suspension test.
abstract: The modulation of N-methyl-D-aspartate receptor (NMDAR) and L-arginine/nitric oxide (NO) pathway is a therapeutic strategy for treating depression and neurologic disorders that involves excitotoxicity. Literature data have reported that creatine exhibits antidepressant and neuroprotective effects, but the implication of NMDAR and L-arginine/nitric oxide (NO) pathway in these effects is not established. This study evaluated the influence of pharmacological agents that modulate NMDAR/L-arginine-NO pathway in the anti-immobility effect of creatine in the tail suspension test (TST) in mice. The NOx levels and cellular viability in hippocampal and cerebrocortical slices of creatine-treated mice were also evaluated. The anti-immobility effect of creatine (10 mg/kg, po) in the TST was abolished by NMDA (0.1 pmol/mouse, icv), D-serine (30 µg/mouse, icv, glycine-site NMDAR agonist), arcaine (1 mg/kg, ip, polyamine site NMDAR antagonist), L-arginine (750 mg/kg, ip, NO precursor), SNAP (25 μg/mouse, icv, NO donor), L-NAME (175 mg/kg, ip, non-selective NOS inhibitor) or 7-nitroindazole (50 mg/kg, ip, neuronal NOS inhibitor), but not by DNQX (2.5 µg/mouse, icv, AMPA receptor antagonist). The combined administration of sub-effective doses of creatine (0.01 mg/kg, po) and NMDAR antagonists MK-801 (0.001 mg/kg, po) or ketamine (0.1 mg/kg, ip) reduced immobility time in the TST. Creatine (10 mg/kg, po) increased cellular viability in hippocampal and cerebrocortical slices and enhanced hippocampal and cerebrocortical NO x levels, an effect potentiated by L-arginine or SNAP and abolished by 7-nitroindazole or L-NAME. In conclusion, the anti-immobility effect of creatine in the TST involves NMDAR inhibition and enhancement of NO levels accompanied by an increase in neural viability.
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianópolis, SC, 88040-900, Brazil.
authors.forename: Mauricio P
authors.initials: MP
authors.lastname: Cunha
authors.forename: Francis L
authors.initials: FL
authors.lastname: Pazini
authors.forename: Fabiana K
authors.initials: FK
authors.lastname: Ludka
authors.forename: Julia M
authors.initials: JM
authors.lastname: Rosa
authors.forename: Ágatha
authors.initials: Á
authors.lastname: Oliveira
authors.forename: Josiane
authors.initials: J
authors.lastname: Budni
authors.forename: Ana B
authors.initials: AB
authors.lastname: Ramos-Hryb
authors.forename: Vicente
authors.initials: V
authors.lastname: Lieberknecht
authors.forename: Luis E B
authors.initials: LE
authors.lastname: Bettio
authors.forename: Maria D
authors.initials: MD
authors.lastname: Martín-de-Saavedra
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.forename: Carla I
authors.initials: CI
authors.lastname: Tasca
authors.forename: Ana Lúcia S
authors.initials: AL
authors.lastname: Rodrigues
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001120:Arginine / Q000378:metabolism*; D003401:Creatine / Q000494:pharmacology*; D003863:Depression / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D005260:Female; D019417:Hindlimb Suspension; D006801:Humans; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000928:Antidepressive Agents; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D001120:Arginine; D003401:Creatine