Disruption of a2ar-d2r heteroreceptor complexes after A2AR transmembrane 5 peptide administration enhances cocaine self-administration in rats
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Antagonistic allosteric A2AR-D2R receptor-receptor interactions in heteroreceptor complexes counteract cocaine self-administration and cocaine seeking in rats as seen in biochemical and behavioral experiments. It was shown that the human A2AR transmembrane five (TM5) was part of the interface of the human A2AR-D2R receptor heteromer. In the current paper, the rat A2AR synthetic TM5 (synthTM5) peptide disrupts the A2AR-D2R heteroreceptor complex in HEK293 cells as shown by the bioluminescence resonance energy transfer method. Rat A2AR synthTM5 peptide, microinjected into the nucleus accumbens, produced a complete counteraction of the inhibitory effects of the A2AR agonist CGS21680 on cocaine self-administration. It was linked to a disappearance of the accumbal A2AR-D2R heteroreceptor complexes and the A2AR agonist induced inhibition of D2R recognition using proximity ligation assay and biochemical binding techniques. However, possible effects of the A2AR synthTM5 peptide on accumbal A2AR-D3R and A2AR-D4R heteroreceptor complexes remain to be excluded. Evidence is provided that accumbal A2AR-D2R-like heteroreceptor complexes with their antagonistic receptor-receptor interactions can be major targets for treatment of cocaine use disorder.
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The primary antibodies used for in situ PLA were previously validated for immunohistochemistry in rat brain tissue and HEK293 cell lines.
“These primary antibodies were previously validated for immunohistochemistry in rat brain tissue and HEK293 cell lines ((Borroto-Escuela et al., 2017b; Borroto-Escuela et al., 2018; Feltmann et al., 2018)).”
From Evidence for the existence of facilitatory interactions between the dopamine D2 receptor and the oxytocin receptor in the amygdala of the rat relevance for anxiolytic actions (2023) · cites this paper as Borroto-Escuela et al., 2018
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Jastrzębski, M. K., Wnorowski, A., Wojnicki, K., Asim, A., & Kaczor, A. A. (2026) · Methods · doi:10.1016/j.ymeth.2026.04.012
Mechanistic and therapeutic insights into class A GPCR dimers in neuropsychiatric disorders
Wang, Z., Wang, L., & Zhang, S. (2026) · npj Drug Discovery. · doi:10.1038/s44386-026-00049-2
- Authors
- Borroto-Escuela, D. O., Wydra, K., Li, X., Rodriguez, D., Carlsson, J., Jastrzębska, J., Filip, M., & Fuxe, K.
- Affiliations
- Maj Institute of Pharmacology (PL)
- Jilin University (CN)
- Uppsala University (SE)
- Corresponding author
- Wydra, Karolina
- Li, Xiang
- Jastrzębska, Joanna
- Venue
- Molecular Neurobiology
- Published
- 2018-01-30
- Volume
- 55
- Issue
- 8
- Pages
- 7038-7048
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- PMC
- PMC6061166
- OpenAlex
- W2793853342
- Cited by
- 58
- References
- 29
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 3 · 2023: 7 · 2022: 9 · 2021: 8 · 2020: 4 · 2019: 10 · 2018: 8
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Neurobiology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
- Funders
- Vetenskapsrådet (62X-00715-50-3, 2013-5708)
- Parkinsonfonden
- AFA Försäkring (130328)
- Hjärnfonden (FO2016-0302)
- Karolinska Institutet Forskningsstiftelser (2016-2017)
- Åke Wibergs stiftelse
- Science for Life Laboratory
- Sven och Lilly Lawski Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Keywords
- adenosine A2A receptor, dopamine D2 receptor, receptor heteromers, cocaine self-administration, cocaine seeking, CGS 21680, nucleus accumbens, cocaine dependence, adenosine signaling
- MeSH terms
- Amino Acid Sequence, Animals, Cocaine, Humans, Male, Peptides, Self Administration, Rats, Sprague-Dawley, Receptors, Dopamine D2, DNA, Complementary, Fluorescence Resonance Energy Transfer, Receptor, Adenosine A2A, HEK293 Cells
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