The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
Caffeine acts through neuronal adenosine A 2A receptors to prevent mood and memory dysfunction triggered by chronic stress
Open accessAbstract
Significance: Epidemiological studies show that individuals exposed to repeated stress, a major trigger of depression, increase their caffeine intake, which correlates inversely with the incidence of depression. However, the mechanism underlying this protective effect is unknown. We used an animal model of chronic unpredictable stress (CUS) to show that caffeine prevents the maladaptive changes caused by CUS in a manner mimicked by the selective blockade of adenosine A 2A receptors (A 2A R). CUS enhanced A 2A R in synapses, and the selective elimination of neuronal A 2A R abrogated CUS modifications. Moreover, A 2A R blockade also afforded a therapeutic benefit, paving the way to consider A 2A R blockers as a strategy to manage the negative impact of chronic stress on mood and memory.
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“Moreover, animal experiments have demonstrated that A 2A R are upregulated in chronic stress animal models. 102”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [102]
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Cites
Physiology and neurobiology of stress and adaptation: central role of the brain
McEwen, B. S. (2007) · Physiological Reviews · doi:10.1152/physrev.00041.2006 · Cited by 5,429 · cited 6×
“Compared with nonstressed (control) mice (noncheckered bars), the mice subjected to CUS (checkered bars) displayed increased immobility in the forced-swimming test [F(2,36) = 182.”
BackgroundResultInfluentialStress and the brain: from adaptation to disease
de Kloet, E. R., Joëls, M., & Holsboer, F. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1683 · Cited by 4,621
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Synaptic Dysfunction in Depression: Potential Therapeutic Targets
Duman, R. S., & Aghajanian, G. K. (2012) · Science · doi:10.1126/science.1222939 · Cited by 1,651 · cited 2×
“However, the data are compatible with A2AR having a key role in glutamatergic terminals defining the synaptic dysfunction underlying the behavioral alterations associated with repeated stress (26, 27).”
The stressed hippocampus, synaptic plasticity and lost memories
Kim, J. J., & Diamond, D. M. (2002) · Nature Reviews Neuroscience · doi:10.1038/nrn849 · Cited by 1,543
The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission
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Self-citationNeuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade
Cunha, R. A. (2005) · Purinergic Signalling · doi:10.1007/s11302-005-0649-1 · Cited by 555
Self-citationChronic stress alters synaptic terminal structure in hippocampus
Magariños, A. M., Verdugo, J. M. G., & McEwen, B. S. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.25.14002 · Cited by 543
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Major depressive disorder: hypothesis, mechanism, prevention and treatment
Cui, L., Li, S., Wang, S., Wu, X., Liu, Y., Yu, W., Wang, Y., Tang, Y., Xia, M., & Li, B. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01738-y · Cited by 1,244
“102 Additionally, neuronal A1 receptors exhibit hypofunction caused by a decrease in astrocyte-derived adenosine levels; 103 this decrease, as well as depressive-like behavior, can be reversed by certain antidepressants.”
BackgroundPharmacology of Adenosine Receptors: The State of the Art
Borea, P. A., Gessi, S., Merighi, S., Vincenzi, F., & Varani, K. (2018) · Physiological Reviews · doi:10.1152/physrev.00049.2017 · Cited by 783
How does adenosine control neuronal dysfunction and neurodegeneration?
Cunha, R. A. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13724 · Cited by 456
Self-citationPurinergic Signalling: Therapeutic Developments
Burnstock, G. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00661 · Cited by 422
Date Palm Tree (Phoenix dactylifera L.): Natural Products and Therapeutic Options
Al-Alawi, R. A., Al-Mashiqri, J. H., Al-Nadabi, J. S. M., Al-Shihi, B. I., & Baqi, Y. (2017) · Frontiers in Plant Science · doi:10.3389/fpls.2017.00845 · Cited by 336
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Metadata
- Authors
- Kaster, M. P., Machado, N. J., Silva, H. B., Nunes, A., Ardais, A. P., Santana, M., Baqi, Y., Müller, C. E., Rodrigues, A. L. S., Porciúncula, L. O., Chen, J. F., Tomé, Â. R., Agostinho, P., Canas, P. M., & Cunha, R. A.
- Affiliations
- Universidade Federal de Santa Catarina (BR)
- Centro de Neurociências e Biologia Celular (PT)
- Universidade Federal do Rio Grande do Sul (BR)
- University of Bonn (DE)
- Boston University (US)
- University of Coimbra (PT)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-06-08
- Volume
- 112
- Issue
- 25
- Pages
- 7833-7838
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4485143
- OpenAlex
- W1591120748
- Cited by
- 312
- References
- 48
- Citations by year
- 2026: 24 · 2025: 28 · 2024: 23 · 2023: 26 · 2022: 33 · 2021: 36 · 2020: 26 · 2019: 29 · 2018: 41 · 2017: 19 · 2016: 17 · 2015: 10
- FWCI
- 13.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Brain and Behavior Research Foundation (2014 NARSAD INDEPENDENT INVESTIGATOR GRANT)
- DOD | Defense Advanced Research Projects Agency (W911NF-10-1-0059)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- caffeine, adenosine A2A receptor, chronic unpredictable mild stress, depression, anxiety, memory impairment, hippocampus, synaptic plasticity, glutamatergic terminals, SNAP-25, syntaxin, VGLUT1, adenosine A2A receptor antagonists, neuroprotection
- MeSH terms
- Animals, Caffeine, Male, Memory Disorders, Mice, Inbred C57BL, Neurons, Stress, Psychological, Mood Disorders, Receptor, Adenosine A2A, Mice
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