title: Role of P2X7 Receptor in an Animal Model of Mania Induced by D-Amphetamine.
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.
authors.affiliation: 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.|Bipolar Disorder Program and Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, 90035-003, Brazil.|INCT of Translational Medicine, Porto Alegre, Brazil.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gubert
authors.affiliation: Bipolar Disorder Program and Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, 90035-003, Brazil.|INCT of Translational Medicine, Porto Alegre, Brazil.
authors.forename: Gabriel Rodrigo
authors.initials: GR
authors.lastname: Fries
authors.affiliation: 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.|Bipolar Disorder Program and Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, 90035-003, Brazil.|INCT of Translational Medicine, Porto Alegre, Brazil.
authors.forename: Bianca
authors.initials: B
authors.lastname: Pfaffenseller
authors.affiliation: Bipolar Disorder Program and Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, 90035-003, Brazil.|INCT of Translational Medicine, Porto Alegre, Brazil.|Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.
authors.forename: Pâmela
authors.initials: P
authors.lastname: Ferrari
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.
authors.forename: Robson
authors.initials: R
authors.lastname: Coutinho-Silva
authors.affiliation: Instituto de Toxicologia e Farmacologia, Faculdade de Farmácia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, 90619-900, Brazil.
authors.forename: Fernanda Bueno
authors.initials: FB
authors.lastname: Morrone
authors.affiliation: Bipolar Disorder Program and Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, 90035-003, Brazil.|INCT of Translational Medicine, Porto Alegre, Brazil.
authors.forename: Flávio
authors.initials: F
authors.lastname: Kapczinski
authors.affiliation: 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. abattastini@gmail.com.|Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Rua Ramiro Barcelos, 2600-anexo, CEP, Porto Alegre, RS, 90035-003, Brazil. abattastini@gmail.com.
authors.forename: Ana Maria Oliveira
authors.initials: AMO
authors.lastname: Battastini
mesh_terms: D000818:Animals; D001714:Bipolar Disorder / Q000139:chemically induced* / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003913:Dextroamphetamine / Q000633:toxicity*; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D058913:Purinergic Agonists / Q000494:pharmacology; D058914:Purinergic Antagonists / Q000494:pharmacology; D058486:Receptors, Purinergic P2X7 / Q000502:physiology*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D058913:Purinergic Agonists; D058914:Purinergic Antagonists; D058486:Receptors, Purinergic P2X7; D017392:Thiobarbituric Acid Reactive Substances; D003913:Dextroamphetamine
keywords: Bipolar disorder; D-amphetamine; Neuroinflammation; P2X7 receptor