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Antidepressant-like effect of guanosine involves activation of AMPA receptor and BDNF/TrkB signaling

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Abstract

Guanosine is a purine nucleoside that has been shown to exhibit antidepressant effects, but the mechanisms underlying its effect are not well established. We investigated if the antidepressant-like effect induced by guanosine in the tail suspension test (TST) in mice involves the modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, voltage-dependent calcium channel (VDCC), and brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway. We also evaluated if the antidepressant-like effect of guanosine is accompanied by an acute increase in hippocampal and prefrontocortical BDNF levels. Additionally, we investigated if the ability of guanosine to elicit a fast behavioral response in the novelty suppressed feeding (NSF) test is associated with morphological changes related to hippocampal synaptogenesis. The antidepressant-like effect of guanosine (0.05 mg/kg, p.o.) in the TST was prevented by DNQX (AMPA receptor antagonist), verapamil (VDCC blocker), K-252a (TrkBantagonist), or BDNF antibody. Increased P70S6K phosphorylation and higher synapsin I immunocontent in the hippocampus, but not in the prefrontal cortex, were observed 1 h after guanosine administration. Guanosine exerted an antidepressant-like effect 1, 6, and 24 h after its administration, an effect accompanied by increased hippocampal BDNF level. In the prefrontal cortex, BDNF level was increased only 1 h after guanosine treatment. Finally, guanosine was effective in the NSF test (after 1 h) but caused no alterations in dendritic spine density and remodeling in the ventral dentate gyrus (DG). Altogether, the results indicate that guanosine modulates targets known to be implicated in fast antidepressant behavioral responses (AMPA receptor, VDCC, and TrkB/BDNF pathway).

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Acknowledgements

The authors would like to thank the Multiuser Laboratory for Biological Studies (LAMEB), Central Laboratory of Electron Microscopy (LCME) and the technical staff, UFSC for support. Bettio LE was supported by a Michael Smith Foundation for Health Research (MSFHR) fellowship.

Data availability statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Funding

This study was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil) #449436/2014-4, #310113/2017-2, and Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES). RBL and ALSR are recipients of CNPq Research Productivity Fellowship.

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

    Priscila B. Rosa, Luis E. B. Bettio, Vivian B. Neis, Morgana Moretti, Fernanda N. Kaufmann, Mauren K. Tavares, Isabel Werle, Yasmim Dalsenter, Nicolle Platt, Axel F. Rosado, Daiane B. Fraga, Isabella A. Heinrich, Andiara E. Freitas, Rodrigo B. Leal & Ana Lúcia S. Rodrigues

  2. Division of Medical Sciences, University of Victoria, Victoria, BC, Canada

    Luis E. B. Bettio

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  1. Priscila B. Rosa
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Correspondence to Ana Lúcia S. Rodrigues.

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Ethical approval

All experiments were performed in accordance with the Guidelines of Ethic Committee on Animal Use of the Federal University of Santa Catarina (CEUA/UFSC) the guidelines laid down by the NIH (NIH Guide for the Care and Use of Laboratory Animals) in the USA. The CEUA/UFSC has approved all experimental protocols (approval numbers PP00795 and 7485180518 protocol).

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Rosa, P.B., Bettio, L.E.B., Neis, V.B. et al. Antidepressant-like effect of guanosine involves activation of AMPA receptor and BDNF/TrkB signaling. Purinergic Signalling 17, 285–301 (2021). https://doi.org/10.1007/s11302-021-09779-6

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