Reduced P2X receptor levels are associated with antidepressant effect in the learned helplessness model
Open accessAbstract
Purinergic receptors, especially P2RX, are associated to the severity of symptoms in patients suffering from depressive and bipolar disorders, and genetic deletion or pharmacological blockade of P2RX7 induces antidepressant-like effect in preclinical models. However, there is scarce evidence about the alterations in P2RX7 or P2RX4 levels and in behavioral consequences induced by previous exposure to stress, a major risk factor for depression in humans. In the present study, we evaluated the effect of imipramine (IMI) on P2RX7 and P2RX4 levels in dorsal and ventral hippocampus as well as in the frontal cortex of rats submitted to the pretest session of learned helplessness (LH) paradigm. Repeated, but not acute administration of IMI (15 mg/kg ip) reduced the levels of both P2RX7 and P2RX4 in the ventral, but not in dorsal hippocampus or frontal cortex. In addition, we tested the effect of P2RX7/P2RX4 antagonist brilliant blue G (BBG: 25 or 50 mg/kg ip) on the LH paradigm. We observed that repeated (7 days) but not acute (1 day) treatment with BBG (50 mg) reduced the number of failures to escape the shocks in the test session, a parameter mimicked by the same regimen of IMI treatment. Taken together, our data indicates that pharmacological blockade or decrease in the expression of P2RX7 is associated to the antidepressant-like behavior observed in the LH paradigm after repeated drug administration.
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Antidepressant treatment decreased P2X7 receptor expression in the ventral hippocampus of stressed animals.
“Corroborating this hypothesis, antidepressant treatment decreased P2X7 receptor expression in the ventral hippocampus of stressed animals [146].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [146]
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Silveira, K. M., & Joca, S. R. L. (2022) · Neuromethods · doi:10.1007/978-1-0716-2748-8_9 · Cited by 6 · see citing works
Self-citationIring-Varga, B., Baranyi, M., Gölöncsér, F., Tod, P., & Sperlágh, B. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1241406 · Cited by 4 · see citing works
Rivi, V., Batabyal, A., Pelé, G., Yakubets, K., Dominici, R., Blom, J. M. C., Tascedda, F., Benatti, C., & Lukowiak, K. D. (2025) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/j.cbpb.2025.111140 · Cited by 4 · see citing works
Antidepressants as modulators of P2X7 receptor activity
Vidal, V. N., Teixeira, G. P., Faria, J. V., Oliveira, J. A. D. S., Bello, M. L., Rocha, L., & Faria, R. X. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.12.042 · Cited by 1 · see citing works
Silveira, K. M., Sartim, A. G., Vieira, L. S., Lisboa, S. F. D. S., Wegener, G., & Joca, S. R. L. (2022) · Acta Neuropsychiatrica · doi:10.1017/neu.2022.24
Self-citationPurinergic Signaling in Depression
Ribeiro, D. E., Kaster, M. P., Ulrich, H., Lisboa, S. F. D. S., & Joca, S. R. L. (2023) · Springer eBooks · doi:10.1007/978-3-031-26945-5_7
Self-citationExtracellular ATP in psychiatric disorders
von Mücke-Heim, I.-A., & Deussing, J. M. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-30250-3.00015-1
- Authors
- Ribeiro, D. E., Casarotto, P. C., Staquini, L., Pinto e Silva, M. A., Biojone, C., Wegener, G., & Joca, S.
- Affiliations
- Universidade de São Paulo (BR)
- University of Helsinki (FI)
- Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
- Aarhus University (DK)
- Venue
- PeerJ
- Publisher
- PeerJ
- Published
- 2019-10-21
- Volume
- 7
- Pages
- e7834
- ISSN
- 2167-8359 (ISSN-L)
- PMC
- PMC6812674
- OpenAlex
- W2980612713
- Cited by
- 21
- References
- 77
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 1 · 2023: 5 · 2022: 5 · 2021: 2 · 2020: 2
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PeerJ (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Työväentutkimus Vuosikirja (submittedVersion)
- Scopus (Elsevier) (submittedVersion)
- Funders
- State of São Paulo Research Foundation (2013/01737-7)
- Aarhus University Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- P2X7 receptor, P2X4 receptor, purinergic receptors, antidepressant effects, learned helplessness, imipramine, Brilliant Blue G, dorsal hippocampus, ventral hippocampus, frontal cortex, stress, depression, receptor expression levels
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