Heterodimer of A2A and oxytocin receptors regulating glutamate release in adult striatal astrocytes
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BACKGROUND: Roles of astrocytes in the modulatory effects of oxytocin (OT) in central nervous system are increasingly considered. Nevertheless, OT effects on gliotransmitter release have been neglected. METHODS: In purified astrocyte processes from adult rat striatum, we assessed OT receptor (OTR) and adenosine A2A receptor expression by confocal analysis. The effects of receptors activation on glutamate release from the processes were evaluated; A2A-OTR heteromerization was assessed by co-immunoprecipitation and PLA. Structure of the possible heterodimer of A2A and OT receptors was estimated by a bioinformatic approach. RESULTS: Both A2A and OT receptors were expressed on the same astrocyte processes. Evidence for A2A-OTR receptor-receptor interaction was obtained by measuring the release of glutamate: OT inhibited the evoked glutamate release, while activation of A2A receptors, per se ineffective, abolished the OT effect. Biochemical and biophysical evidence for A2A-OTR heterodimers on striatal astrocytes was also obtained. The residues in the transmembrane domains 4 and 5 of both receptors are predicted to be mainly involved in the heteromerization. CONCLUSIONS: When considering effects of OT in striatum, modulation of glutamate release from the astrocyte processes and of glutamatergic synapse functioning, and the interaction with A2A receptors on the astrocyte processes should be taken into consideration.
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In the striatum, OXTR activation on astrocytes inhibits glutamate release, and D2R-OXTR heterocomplexes facilitate dopaminergic signaling.
“In the striatum, OXTR activation on astrocytes inhibits glutamate release (Amato et al., 2022), and D2R-OXTR heterocomplexes facilitate dopaminergic signaling (Hernandez-Mondragon et al., 2023; Pérez de la Mora et al., 2016).”
From Music's context-dependent influence on oxytocin, social bonding, and emotion regulation: a systematic review (2026) · cites this paper as Amato et al., 2022
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Adenosine A2AReceptors in Substance Use Disorders: A Focus on Cocaine
Wydra, K., Gawliński, D., Gawlińska, K., Frankowska, M., Borroto‐Escuela, D. O., Fuxé, K., & Filip, M. (2020) · Cells · doi:10.3390/cells9061372 · Cited by 20 · see citing works
Urotensin II receptor and acetylcholine release from mouse cervical spinal cord nerve terminals
Bruzzone, F., Cervetto, C., Mazzotta, M. C., Bianchini, P., Ronzitti, E., Leprince, J., Diaspro, A., Maura, G., Vallarino, M. C., Vaudry, H., et al. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.06.070 · Cited by 19 · see citing works
GalaxyHeteromer: protein heterodimer structure prediction by template-based and ab initio docking
Park, T., Won, J., Baek, M., & Seok, C. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab422 · Cited by 17 · see citing works
Adenosine A2A receptors and their role in drug addiction
Brown, R. M., & Short, J. L. (2008) · Journal of Pharmacy and Pharmacology · doi:10.1211/jpp/60.11.0001 · Cited by 16 · see citing works
Astrocytes and presynaptic plasticity in the striatum: Evidence and unanswered questions
Dvorzhak, A., Melnick, I. V., & Grantyn, R. (2017) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2017.01.001 · Cited by 15 · see citing works
Neurotransmitter receptor heteromers in neurodegenerative diseases and neural plasticity
Franco, R. (2008) · Journal of Neural Transmission · doi:10.1007/s00702-008-0148-y · Cited by 14 · see citing works
Osako, Y., Otsuka, T., Taniguchi, M., Oka, T., & Kaba, H. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(00)01235-0 · Cited by 13 · see citing works
Franchi, A., Pedrazzi, M., Casazza, A. A., Millo, E., Damonte, G., Salis, A., Liessi, N., Onofri, F., Marte, A., Casagrande, S., et al. (2020) · Molecules · doi:10.3390/molecules25194385 · Cited by 5 · see citing works
Oxytocin Receptor-Mediated Signaling in Astrocytes
Meinung, C.-P. (2020) · University of Regensburg Publication Server (University of Regensburg) · doi:10.5283/epub.43289 · Cited by 3 · see citing works
Guidolin, D., Tortorella, C., Anderlini, D., Marcoli, M., Maura, G., & Agnati, L. F. (2021) · Current Proteomics · doi:10.2174/1570164618999201216112244 · Cited by 3 · see citing works
Flagged first, then by citations
1 of the 104 references couldn’t be matched to a known paper.
Cited by
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Chakraborty, P., Dey, A., Gopalakrishnan, A. V., Swati, K., Ojha, S. K., Prakash, A., Kumar, D., Ambasta, R. K., Jha, N. K., Jha, S. K., et al. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101838 · Cited by 58 · see citing works
Emerging role of astrocytes in oxytocin-mediated control of neural circuits and brain functions
Baudon, A., Creusot, E. C., Althammer, F., Schaaf, C. P., & Charlet, A. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102328 · Cited by 40 · see citing works
Intertwined associations between oxytocin, immune system and major depressive disorder
Jiang, J., Yang, M., Tian, M., Chen, Z., Xiao, L., & Gong, Y. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114852 · Cited by 36 · see citing works
Heteromerization of Dopamine D2 and Oxytocin Receptor in Adult Striatal Astrocytes
Amato, S., Averna, M., Guidolin, D., Ceccoli, C., Gatta, E., Candiani, S., Pedrazzi, M., Capraro, M., Maura, G., Agnati, L. F., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24054677 · Cited by 24 · see citing works
Cervetto, C., Maura, G., Guidolin, D., Amato, S., Ceccoli, C., Agnati, L. F., & Marcoli, M. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109636 · Cited by 24 · see citing works
Purinergic-associated immune responses in neurodegenerative diseases
Carracedo, S., Launay, A., Déchelle-Marquet, P.-A., Faivre, É., Blum, D. L., Delarasse, C., & Boué‐Grabot, É. (2024) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2024.102693 · Cited by 19 · see citing works
Complexity of the Hypothalamic Oxytocin System and its Involvement in Brain Functions and Diseases
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Guidolin, D., Tortorella, C., Marcoli, M., Cervetto, C., Maura, G., & Agnati, L. F. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109509 · Cited by 14 · see citing works
Brain Structure and Function: Insights from Chemical Neuroanatomy
Agnati, L. F., Guidolin, D., Cervetto, C., Maura, G., & Marcoli, M. (2023) · Life · doi:10.3390/life13040940 · Cited by 10 · see citing works
Chu, T.-H., & Tsai, C.-G. (2026) · Frontiers in cognition · doi:10.3389/fcogn.2025.1678665 · Cited by 8 · see citing works
Control of Dopamine Signal in High-Order Receptor Complex on Striatal Astrocytes
Amato, S., Averna, M., Farsetti, E., Guidolin, D., Pedrazzi, M., Gatta, E., Candiani, S., Maura, G., Agnati, L. F., Cervetto, C., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25168610 · Cited by 7 · see citing works
Marcoli, M., Agnati, L. F., Franco, R., Cortelli, P., Anderlini, D., Guidolin, D., Cervetto, C., & Maura, G. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1038874 · Cited by 7 · see citing works
Dual Oxytocin Signals in Striatal Astrocytes
Farsetti, E., Amato, S., Averna, M., Guidolin, D., Pedrazzi, M., Maura, G., Agnati, L. F., Cervetto, C., & Marcoli, M. (2025) · Biomolecules · doi:10.3390/biom15081122 · Cited by 4 · see citing works
Heralding a new era of oxytocinergic research: New tools, new problems?
Althammer, F. (2023) · Journal of Neuroendocrinology · doi:10.1111/jne.13333 · Cited by 4 · see citing works
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Possible roles of heteroreceptor complexes in excitotoxic processes
Guidolin, D., Tortorella, C., Marcoli, M., Cervetto, C., De, R., Maura, G., & Agnati, L. F. (2024) · Exploration of Neuroprotective Therapy · doi:10.37349/ent.2024.00089 · Cited by 3 · see citing works
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A2AR and traumatic brain injury
Zhao, Y., Ning, Y., & Zhou, Y. (2023) · International review of neurobiology · doi:10.1016/bs.irn.2023.07.006
Dual Pathways Coupled to Oxytocin Molecular Signals in Cultured Astrocytes
Farsetti, E., Amato, S., Averna, M., Gatta, E., Guidolin, D., Pedrazzi, M., Lori, L., Matilde, G., Maura, G., Agnati, L. F., et al. (2026) · Cells · doi:10.3390/cells15100950
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Circuit logic of oxytocin and vasopressin complementary actions
Jeanneteau, F. D., Chakraborty, P., Petitjean, H., & Charlet, A. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1875731
- Authors
- Amato, S., Averna, M., Guidolin, D., Pedrazzi, M., Pelassa, S., Capraro, M., Passalacqua, M., Bozzo, M., Gatta, E., Anderlini, D., Maura, G., Agnati, L. F., Cervetto, C., & Marcoli, M.
- Affiliations
- University of Genoa (IT)
- University of Padua (IT)
- The University of Queensland (AU)
- University of Modena and Reggio Emilia (IT)
- Corresponding author
- Cervetto, Chiara
- Marcoli, Manuela
- ORCID
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2022-02-19
- Volume
- 23
- Issue
- 4
- Pages
- 2326
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC8879615
- OpenAlex
- W4214663246
- Cited by
- 23
- References
- 104
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 4 · 2023: 10 · 2022: 3
- FWCI
- 2.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion, other-oa)
- Funders
- FFABR (Fondo di finanziamento per le attività base di ricerca; MIUR-Italy) (FFABR- to C.C. and M.M.)
- Ph.D School of the Department of Experimental Medicine (University of Genova) (contribution 2021 to S.A.)
- MUR (DIFILAB, Grant/Award Number: RBAP11ETKA-005)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- oxytocin receptor, adenosine A2A receptor, receptor heterodimerization, striatal astrocytes, glutamate release, gliotransmitter release, astrocyte processes, oxytocin
- MeSH terms
- Animals, Astrocytes, Corpus Striatum, Male, Oxytocin, Neostriatum, Rats, Sprague-Dawley, Receptors, Oxytocin, Glutamic Acid, Receptor, Adenosine A2A, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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