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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

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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.

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Abbreviations

MTT:

3-(4,5-Dimethylthiazol-2-yl-diphenyltetrazolium bromide

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

dimethylsulfoxide

FST:

Forced Swimming Test

Icv :

Intracerebroventricular

Ip :

Intraperitoneal

L-NAME:

NG-nitro-l-arginine methyl ester

NO:

Nitric oxide

NOS:

Nitric oxide synthase

NMDA:

N-Methyl-D-aspartate

NMDAR:

N-Methyl-D-aspartate receptor

Po:

Per os

SNAP:

S-nitroso-N-acetyl-penicillamine

TST:

Tail suspension test

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Acknowledgments

This study was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES), Fundação de Apoio a Pesquisa Científica e Tecnológica do Estado de Santa Catarina (FAPESC), Rede Instituto Brasileiro de Neurociência (IBN-Net/CNPq), Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC) Project/PRONEX Program (CNPq/FAPESC).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianópolis, SC, 88040-900, Brazil

    Mauricio P. Cunha, Francis L. Pazini, Fabiana K. Ludka, Julia M. Rosa, Ágatha Oliveira, Josiane Budni, Ana B. Ramos-Hryb, Vicente Lieberknecht, Luis E. B. Bettio, Carla I. Tasca & Ana Lúcia S. Rodrigues

  2. Department of Pharmacy, Universidade do Contestado, Canoinhas, SC, Brazil

    Fabiana K. Ludka

  3. Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil

    Josiane Budni

  4. Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, 4-28029, Madrid, Spain

    Maria D. Martín-de-Saavedra & Manuela G. López

  5. Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 4-28029, Madrid, Spain

    Maria D. Martín-de-Saavedra & Manuela G. López

  6. Instituto de Investigación Sanitaria Hospital de la Princesa, 4-28029, Madrid, Spain

    Maria D. Martín-de-Saavedra & Manuela G. López

Authors
  1. Mauricio P. Cunha
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  2. Francis L. Pazini
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  3. Fabiana K. Ludka
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  4. Julia M. Rosa
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  5. Ágatha Oliveira
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  6. Josiane Budni
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  7. Ana B. Ramos-Hryb
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  8. Vicente Lieberknecht
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  9. Luis E. B. Bettio
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  10. Maria D. Martín-de-Saavedra
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  11. Manuela G. López
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  12. Carla I. Tasca
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  13. Ana Lúcia S. Rodrigues
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Corresponding author

Correspondence to Ana Lúcia S. Rodrigues.

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Handling Editor: V. Bolshakov.

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Cunha, M.P., Pazini, F.L., Ludka, F.K. et al. 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. Amino Acids 47, 795–811 (2015). https://doi.org/10.1007/s00726-014-1910-0

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  • DOI: https://doi.org/10.1007/s00726-014-1910-0

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