Antidepressant-like effect induced by P2X7 receptor blockade in FSL rats is associated with BDNF signalling activation

Autor(es)

Ribeiro, Deidiane E. ^{[1, 2, 3, 4]} ; Mueller, Heidi K. ^[3] ; Elfving, Betina ^[3] ; Eskelund, Amanda ^[3] ; Joca, Samia R. L. ^{[3, 5, 4]} ; Wegener, Gregers ^{[3, 6]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Pharmacol, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Chem, Dept Biochem, Sao Paulo - Brazil

^[3] Aarhus Univ, Dept Clin Med, Aarhus - Denmark

^[4] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Chem & Phys, Ave Cafe Sn, BR-14040903 Ribeirao Preto - Brazil

^[5] Aarhus Univ, Aarhus Inst Adv Studies, Aarhus - Denmark

^[6] Aarhus Univ, Dept Clin Med, AUGUST Ctr, Aarhus - Denmark

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF PSYCHOPHARMACOLOGY; v. 33, n. 11, p. 1436-1446, NOV 2019.
• Citações Web of Science: 1

Resumo

Background: P2X7 receptors (P2X7R) are ligand-gated ion channels activated by adenosine 5'-triphosphate (ATP), which are involved in processes that are dysfunctional in stress response and depression, such as neurotransmitter release, and neuroimmune response. Genetic and pharmacological inhibition of the P2X7R induce antidepressant-like effects in animals exposed to stress. However, the effect of P2X7R antagonism in an animal model of depression based on selective breeding has not previously been studied, and the mechanism underling the antidepressant-like effect induced by the P2X7R blockade remains unknown. Aims: The present study aimed to: (1) determine whether P2X7R blockade induces antidepressant-like effects in the Flinders Sensitive Line (FSL) rats and, (2) investigate whether brain-derived neurotrophic factor (BDNF) signalling in the frontal cortex and hippocampus is involved in this effect. Methods: FSL and the control Flinders Resistant Line (FRL) rats were treated with vehicle or the P2X7R antagonist A-804598 (3, 10 or 30 mg/Kg/day) for 1 or 7 days before being exposed to the forced swim test (FST). After the behavioural test, animals were decapitated, their brains were removed and the frontal cortex, ventral and dorsal hippocampus were dissected for BDNF signalling analysis. Results: We found that repeated treatment with A-804598 (30 mg/Kg) reduced the immobility time in the FST and activated the BDNF signalling in the ventral hippocampus of FSL rats. Conclusions: P2X7R blockade induces an antidepressant-like effect associated with increased levels of BDNF-AKT-p70 S6 kinase in the ventral hippocampus, which may be mediated by tropomyosin-related kinase B (TRKB) receptor activation supporting the notion of P2X7R antagonism as a potential new antidepressant strategy. (AU)

• Processo FAPESP: 13/01737-7 - Envolvimento do sistema purinérgico na mediação de respostas comportamentais induzidas pelo estresse e no mecanismo de ação de drogas antidepressivas
• Beneficiário: Deidiane Elisa Ribeiro
• Linha de fomento: Bolsas no Brasil - Doutorado