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Role of P2X7 Receptor in an Animal Model of Mania Induced by D-Amphetamine

Molecular Neurobiology volume 53, pages 611–620 (2016)Cite this article

Abstract

The objective of this study was to explore the association between the P2X7 purinergic receptor (P2X7R) and neuroinflammation using a preclinical model of acute bipolar mania. We analyzed the modulatory effects of P2X7R agonist (3′-O-(4-benzoyl)benzoyl-adenosine 5′-triphosphate, BzATP) and antagonists (brilliant blue, BBG and 3-[[5-(2,3 dichlorophenyl)-1H-tetrazol-1-yl]methyl]pyridine hydrochloride, A438079) on assessments related to behavior (locomotor activity), neuroinflammation (interleukin-1 beta, IL-1β; tumor necrosis factor alpha, TNF-α; and interleukin- 6, IL-6), oxidative stress (thiobarbituric acid reactive substances, TBARS) and neuroplasticity (brain-derived neurotrophic factor, BDNF) markers in a pharmacological model of mania induced by acute and chronic treatment with D-amphetamine (AMPH) (2 mg/kg) in mice. An apparent lack of responsiveness to AMPH was observed in terms of the locomotor activity in animals with blocked P2X7R or with genetic deletion of P2X7R in knockout (P2X7R−/−) mice. Likewise, P2X7R participated in the AMPH-induced increase of the proinflammatory and excitotoxic environment, as demonstrated by the reversal of IL-1β, TNF-α, and TBARS levels caused by P2X7R blocking. Our results support the hypothesis that P2X7R plays a role in the neuroinflammation induced by AMPH in a preclinical model of mania, which could explain the altered behavior. The present data suggest that P2X7R may be a therapeutic target related to the neuroinflammation reported in bipolar disorder.

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Acknowledgments

CG, GRF, and PF are recipients of scholarships from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). BP is a scholarship recipient from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). This study was supported by the National Science and Technology Institute for Translational Medicine, funded by CNPq and by Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (FIPE-HCPA).

Conflict of Interest

CG, GRF, BP, PF, RCS, and FBM declare no possible conflicts of interest, financial or otherwise, or grants or other forms of financial support. AMOB has received grant/research from CNPq. FK has received grant/research support from Astra-Zeneca, Eli Lilly, Janssen-Cilag, Servier, CNPq, CAPES, NARSAD, and the Stanley Medical Research Institute; has been a member of speakers boards for Astra-Zeneca, Eli Lilly, Janssen, and Servier; and has served as a consultant for Servier.

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Affiliations

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

    Carolina Gubert, Bianca Pfaffenseller & Ana Maria Oliveira Battastini

  2. Bipolar Disorder Program and Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, 90035-003, Brazil

    Carolina Gubert, Gabriel Rodrigo Fries, Bianca Pfaffenseller, Pâmela Ferrari & Flávio Kapczinski

  3. INCT of Translational Medicine, Porto Alegre, Brazil

    Carolina Gubert, Gabriel Rodrigo Fries, Bianca Pfaffenseller, Pâmela Ferrari & Flávio Kapczinski

  4. Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil

    Pâmela Ferrari & Robson Coutinho-Silva

  5. Instituto de Toxicologia e Farmacologia, Faculdade de Farmácia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, 90619-900, Brazil

    Fernanda Bueno Morrone

  6. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Rua Ramiro Barcelos, 2600–anexo, CEP, Porto Alegre, RS, 90035-003, Brazil

    Ana Maria Oliveira Battastini

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  1. Carolina Gubert
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  2. Gabriel Rodrigo Fries
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Gubert, C., Fries, G.R., Pfaffenseller, B. et al. Role of P2X7 Receptor in an Animal Model of Mania Induced by D-Amphetamine. Mol Neurobiol 53, 611–620 (2016). https://doi.org/10.1007/s12035-014-9031-z

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Keywords

  • Bipolar disorder
  • P2X7 receptor
  • D-amphetamine
  • Neuroinflammation