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P2X7 Purinergic Receptor Is Involved in the Pathophysiology of Mania: a Preclinical Study

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Abstract

The pathophysiology of bipolar disorder remains incompletely elucidated. The purinergic receptor, P2X7 (P2X7R), plays a central role in neuroinflammation, the establishment, and maintenance of microglial activation and neuronal damage/death, all characteristics of bipolar disorder pathology. The present study aims to explore the participation of the P2X7R in a preclinical pharmacological model of mania. We analyzed the modulatory effects of the P2X7R antagonist, brilliant blue, on behavior, monoamines, gene expression, serum purine levels, and cell typing in a pharmacological model of mania induced by d-amphetamine (AMPH) in mice. Our results corroborate an association between the P2X7 receptor and the preclinical animal model of mania, as demonstrated by the decreased responsiveness to AMPH in animals with pharmacologically blocked P2X7R. This study further suggests a possible dopaminergic mechanism for the action of P2X7 receptor antagonism. Additionally, we observed increased peripheral levels of adenosine, a neuroprotective molecule, and increased central expression of Entpd3 and Entpd1 leading to the hydrolysis of ATP, a danger signal, possibly as an attempt to compensate for the damage induced by AMPH. Lastly, P2X7R antagonism in the AMPH model was found to potentially modulate astrogliosis. Our results support the hypothesis that P2X7R plays a vital role in the pathophysiology of mania, possibly by modulating the dopaminergic pathway and astrogliosis, as reflected in the behavioral changes observed. Taken together, this study suggests that a purinergic system imbalance is associated with the AMPH-induced preclinical animal model of mania. P2X7R may represent a promising molecular therapeutic target for bipolar disorder.

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Acknowledgments

CG and RA were recipients of scholarships from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). CEJM is recipient of scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES). PVSM is supported by a CNPq productivity fellowship. Currently CG is recipient of a Post-Doctoral Fellowship (PDE–Pos Doutorado no Exterior) from CNPq–Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, of the Ministry of Science, Technology, Innovation, Communication of Brazil and a University of Melbourne Early Career Researcher Award.

Funding

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES)-Finance Code 001. This work was also supported by grants from the National Science and Technology Institute for Translational Medicine (INCT-TM) (Project 573671/2008-7), INCT for excitotoxicity and neuroprotection (INCT-EN) (Project 465671/2014-4), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (Project No 303264/2013-6), and Fundo de Incentivo à Pesquisa–Hospital de Clínicas de Porto Alegre (FIPE-HCPA). The funding agencies did not have any role in study design, data collection and analysis, the decision to publish, or manuscript preparation. Dr. Kapczinski reports personal fees from Daiichi sankyo, personal fees from Janssen-Cilag, grants from Stanley Medical Research Institute 07TGF/1148, grants from INCT-CNPq 465458/2014-9, grants from Canada Foundation for Innovation-CFI, outside the submitted work.

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Authors and Affiliations

  1. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600–anexo, Porto Alegre, RS, 90035-003, Brazil

    Carolina Gubert, Roberta Andrejew, Juliete Scholl, Fabricio Figueiro & Ana Maria Oliveira Battastini

  2. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, 3010, Australia

    Carolina Gubert

  3. Instituto de Toxicologia e Farmacologia, Pontifícia Universidade Católica do Rio Grande do Sul, Avenida Ipiranga, 6681, Porto Alegre, RS, 90619-900, Brazil

    Carlos Eduardo Leite

  4. Programa de Pós-Graduação em Ciências do Movimento Humano, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Cesar Eduardo Jacintho Moritz

  5. Department of Psychiatry and Behavioral Sciences, MacMaster University, Hamilton, Canada

    Flávio Kapczinski

  6. Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, 90035-003, Brazil

    Pedro Vieira da Silva Magalhães

  7. Departamento de Psiquiatria, Universidade Federal Rio Grande do Sul, Porto Alegre, RS, 90035-903, Brazil

    Pedro Vieira da Silva Magalhães

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  1. Carolina Gubert
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  2. Roberta Andrejew
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  3. Carlos Eduardo Leite
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  4. Cesar Eduardo Jacintho Moritz
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  5. Juliete Scholl
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  6. Fabricio Figueiro
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  7. Flávio Kapczinski
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  8. Pedro Vieira da Silva Magalhães
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  9. Ana Maria Oliveira Battastini
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Corresponding author

Correspondence to Carolina Gubert.

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The experimental procedures reported in this manuscript were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the Brazilian College of Animal Experimentation. The Animal Ethics Committee of the Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil, approved this project under protocol number 15-0192.

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Gubert, C., Andrejew, R., Leite, C.E. et al. P2X7 Purinergic Receptor Is Involved in the Pathophysiology of Mania: a Preclinical Study. Mol Neurobiol 57, 1347–1360 (2020). https://doi.org/10.1007/s12035-019-01817-0

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