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Low doses of ketamine and guanosine abrogate corticosterone-induced anxiety-related behavior, but not disturbances in the hippocampal NLRP3 inflammasome pathway

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Abstract

Rationale

Guanosine has been shown to potentiate ketamine’s antidepressant-like actions, although its ability to augment the anxiolytic effect of ketamine remains to be determined.

Objective

This study investigated the anxiolytic-like effects of a single administration with low doses of ketamine and/or guanosine in mice subjected to chronic administration of corticosterone and the role of NLRP3-driven signaling.

Methods

Corticosterone (20 mg/kg, p.o.) was administered for 21 days, followed by a single administration of ketamine (0.1 mg/kg, i.p.), guanosine (0.01 mg/kg, p.o.), or ketamine (0.1 mg/kg, i.p.) plus guanosine (0.01 mg/kg, p.o.). Anxiety-like behavior and NLRP3-related targets were analyzed 24 h following treatments.

Results

Corticosterone reduced the time spent in the open arms and the central zone in the elevated plus-maze test and open-field test, respectively. Corticosterone raised the number of unsupported rearings and the number and time of grooming, and decreased the latency to start grooming in the open-field test. Disturbances in regional distribution (increased rostral grooming) and grooming transitions (increased aborted and total incorrect transitions) were detected in corticosterone-treated mice. These behavioral alterations were accompanied by increased immunocontent of Iba-1, ASC, NLRP3, caspase-1, TXNIP, and IL-1β in the hippocampus, but not in the prefrontal cortex. The treatments with ketamine, guanosine, and ketamine plus guanosine were effective to counteract corticosterone-induced anxiety-like phenotype, but not disturbances in the hippocampal NLRP3 pathway.

Conclusions

Our study provides novel evidence that low doses of ketamine and/or guanosine reverse corticosterone-induced anxiety-like behavior and shows that the NLRP3 inflammasome pathway is likely unrelated to this response.

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Data availability

All data generated or analyzed during this study are included in this published article.

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Acknowledgements

The authors thank funding agencies CNPq and CAPES for the financial support, and the Laboratório Multiusuário de Estudos em Biologia (LAMEB) for the technical support.

Funding

This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq #310113/2017-2) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Ana Lúcia S. Rodrigues and Manuella P. Kaster are recipients of CNPq Research Productivity Fellowship.

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Authors and Affiliations

  1. Center of Biological Sciences, Neuroscience Postgraduate Program, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil

    Anderson Camargo, Daiane B. Fraga, Manuella P. Kaster & Ana Lúcia S. Rodrigues

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

    Anderson Camargo, Daiane B. Fraga, Julia M. Rosa, Manuella P. Kaster & Ana Lúcia S. Rodrigues

  3. Laboratory of Evaluation of Bioactive Substances, Department of Natural Sciences, Universidade Regional de Blumenau, Blumenau, Santa Catarina, 89030-903, Brazil

    Ana Paula Dalmagro & Ana Lúcia B. Zeni

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  1. Anderson Camargo
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  2. Ana Paula Dalmagro
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Contributions

Ana Lúcia S. Rodrigues: conceptualization, funding acquisition, project administration, resources, and supervision, and revision of the manuscript. Anderson Camargo: data curation, formal analysis, investigation, methodology, project administration, software, and writing the manuscript draft. Ana P. Dalmagro: data curation, formal analysis, investigation, and methodology. Daiane B. Fraga: data curation, formal analysis, investigation, and methodology. Julia M. Rosa: investigation, and methodology. Ana Lúcia B. Zeni: investigation, and methodology. Manuella P. Kaster: conceptualization, investigation, methodology, and writing the manuscript draft.

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Correspondence to Ana Lúcia S. Rodrigues.

Ethics declarations

The procedures used in this study complied with the guidelines on animal care of the UFSC Ethics Committee on the Use of Animals (CEUA), which follow the principles of laboratory animal care from NIH (2011).

Ethical approval

The experiments were performed after approval of the protocol by the Institutional Ethics Committee and according to the National Institute of Health Guide for the Care and Use of Laboratory Animals.

Conflict of interest

The authors declare no competing interests.

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Camargo, A., Dalmagro, A.P., Fraga, D.B. et al. Low doses of ketamine and guanosine abrogate corticosterone-induced anxiety-related behavior, but not disturbances in the hippocampal NLRP3 inflammasome pathway. Psychopharmacology 238, 2555–2568 (2021). https://doi.org/10.1007/s00213-021-05879-8

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