Antidepressant-like effect induced by P2X7 receptor blockade in FSL rats is associated with BDNF signalling
Deidiane E Ribeiro1,2,3,4, Heidi K Müller3, Betina Elfving3
1Department of Pharmacology, School of Medicine of Ribeirão Preto - University of São Paulo, São Paulo, Brazil.
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.
Insights
Blocking P2X7 receptors (P2X7R) shows antidepressant-like effects in a rat model of depression. This effect is linked to increased brain-derived neurotrophic factor (BDNF) signaling in the ventral hippocampus.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- P2X7 receptors (P2X7R), activated by ATP, are implicated in stress response and depression.
- Previous studies show genetic or pharmacological P2X7R inhibition yields antidepressant-like effects in stressed animals.
- The impact of P2X7R antagonism in selectively bred depression models and its underlying mechanisms remain unexplored.
Purpose of the Study:
- To evaluate P2X7 receptor (P2X7R) blockade's antidepressant-like effects in Flinders Sensitive Line (FSL) rats.
- To investigate the involvement of brain-derived neurotrophic factor (BDNF) signaling in the frontal cortex and hippocampus.
Main Methods:
- Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL) rats received vehicle or P2X7R antagonist A-804598.
- Animals were treated for 1 or 7 days before the forced swim test (FST).
- Post-test, brain regions (frontal cortex, ventral/dorsal hippocampus) were analyzed for BDNF signaling.
Main Results:
- Repeated administration of A-804598 (30 mg/Kg) significantly reduced immobility time in FSL rats during the FST.
- This treatment activated BDNF signaling pathways specifically within the ventral hippocampus of FSL rats.
Conclusions:
- P2X7 receptor (P2X7R) blockade demonstrates antidepressant-like effects.
- The observed effects are associated with enhanced BDNF-AKT-p70 S6 kinase signaling in the ventral hippocampus.
- Tropomyosin-related kinase B (TRKB) receptor activation may mediate these effects, suggesting P2X7R antagonism as a novel antidepressant strategy.
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