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Creatine, similarly to ketamine, affords antidepressant-like effects in the tail suspension test via adenosine A1 and A2A receptor activation

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Abstract

The benefits of creatine supplementation have been reported in a broad range of central nervous systems diseases, including depression. A previous study from our group demonstrated that creatine produces an antidepressant-like effect in the tail suspension test (TST), a predictive model of antidepressant activity. Since depression is associated with a dysfunction of the adenosinergic system, we investigated the involvement of adenosine A1 and A2A receptors in the antidepressant-like effect of creatine in the TST. The anti-immobility effect of creatine (1 mg/kg, po) or ketamine (a fast-acting antidepressant, 1 mg/kg, ip) in the TST was prevented by pretreatment of mice with caffeine (3 mg/kg, ip, nonselective adenosine receptor antagonist), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (2 mg/kg, ip, selective adenosine A1 receptor antagonist), and 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)-phenol (ZM241385) (1 mg/kg, ip, selective adenosine A2A receptor antagonist). In addition, the combined administration of subeffective doses of creatine and adenosine (0.1 mg/kg, ip, nonselective adenosine receptor agonist) or inosine (0.1 mg/kg, ip, nucleoside formed by the breakdown of adenosine) reduced immobility time in the TST. Moreover, the administration of subeffective doses of creatine or ketamine combined with N-6-cyclohexyladenosine (CHA) (0.05 mg/kg, ip, selective adenosine A1 receptor agonist), N-6-[2-(3,5-dimethoxyphenyl)-2-(methylphenyl)ethyl]adenosine (DPMA) (0.1 mg/kg, ip, selective adenosine A2A receptor agonist), or dipyridamole (0.1 μg/mouse, icv, adenosine transporter inhibitor) produced a synergistic antidepressant-like effect in the TST. These results indicate that creatine, similarly to ketamine, exhibits antidepressant-like effect in the TST probably mediated by the activation of both adenosine A1 and A2A receptors, further reinforcing the potential of targeting the purinergic system to the management of mood disorders.

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Abbreviations

CHA:

N6-cyclohexyladenosine

DPCPX:

8-cyclopentyl-1,3-dipropylxanthine

DPMA:

N6-[2-(3,5-dimethoxyphenyl)-2-(methylphenyl)ethyl]adenosine

TST:

Tail suspension test

icv :

Intracerebroventricular

ip :

Intraperitoneal

po :

Per os

ZM241385:

4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)-phenol

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Acknowledgments

This study was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), #308723/2013-9, Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES), NENASC project (PRONEX program CNPq/FAPESC).

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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, Julia M. Rosa, Ana B. Ramos-Hryb, Ágatha Oliveira, Manuella P. Kaster & Ana Lúcia S. Rodrigues

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  1. Mauricio P. Cunha
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  2. Francis L. Pazini
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  3. Julia M. Rosa
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  5. Ágatha Oliveira
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  6. Manuella P. Kaster
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  7. Ana Lúcia S. Rodrigues
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Correspondence to Mauricio P. Cunha.

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Cunha, M.P., Pazini, F.L., Rosa, J.M. et al. Creatine, similarly to ketamine, affords antidepressant-like effects in the tail suspension test via adenosine A1 and A2A receptor activation. Purinergic Signalling 11, 215–227 (2015). https://doi.org/10.1007/s11302-015-9446-7

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