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Int J Mol Sci. 2019 Dec 3;20(23). pii: E6100. doi: 10.3390/ijms20236100.

A2AR Transmembrane 2 Peptide Administration Disrupts the A2AR-A2AR Homoreceptor but Not the A2AR-D2R Heteroreceptor Complex: Lack of Actions on Rodent Cocaine Self-Administration.

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Department of Neuroscience, Karolinska Institutet, 16175 Stockholm, Sweden.
Department of Biomolecular Science, Section of Physiology, University of Urbino, Campus Scientifico Enrico Mattei, via Ca' le Suore 2, I-61029 Urbino, Italy.
Grupo Bohío-Estudio, Observatorio Cubano de Neurociencias, Zayas 50, Yaguajay 62100, Cuba.
Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, 31-343 Kraków, Poland.
Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, 752 36 Uppsala, Sweden.
National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.


It was previously demonstrated that rat adenosine A2AR transmembrane V peptide administration into the nucleus accumbens enhances cocaine self-administration through disruption of the A2AR-dopamine (D2R) heteroreceptor complex of this region. Unlike human A2AR transmembrane 4 (TM4) and 5 (TM5), A2AR TM2 did not interfere with the formation of the A2AR-D2R heteroreceptor complex in cellular models using BRET1 assay. A2AR TM2 was proposed to be part of the of the receptor interface of the A2AR homomer instead and was therefore tested in the current article for effects on rat cocaine self-administration using rat A2AR synthetic TM2 peptide bilaterally injected into the nucleus accumbens. The injected A2AR TM2 peptide failed to significantly counteract the inhibitory action of the A2AR agonist CGS 21680 (0.1 mg/Kg) on cocaine self-administration. In line with these results, the microinjected A2AR TM2 peptide did not reduce the number of proximity ligation assay blobs identifying A2AR-D2R heteroreceptor complexes in the nucleus accumbens. In contrast, the A2AR TM2 peptide significantly reduced the number of A2AR-A2AR homoreceptor complexes in the nucleus accumbens. As to effects on the receptor-receptor interactions in the A2AR-D2R heteroreceptor complexes, the A2AR TM2 peptide did not alter the significant increase in the D2R Ki, high values produced by the A2AR agonist CGS 21680 ex vivo in the ventral striatum. The results indicate that the accumbal A2AR-A2AR homomeric complexes are not involved in mediating the A2AR agonist-induced inhibition of cocaine self-administration.


adenosine A2A receptor; allosteric receptor–receptor interactions; cocaine use disorder; dopamine D2 receptor; heteroreceptor complexes; homoreceptor complexes; small interfering peptides: G protein-coupled receptors

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