LAUSR

&NA; Adenosine 2A receptor (A2AR) agonists were indicated to reduce cocaine reward and cocaine seeking mainly through activation of antagonistic allosteric A2AR‐dopamine D2R (D2R) interactions in A2AR‐D2R heteroreceptor complexes. Furthermore, it was shown that modulation of cocaine reward involves antagonistic A2AR‐D2R interactions in the ventral but not the dorsal striatum in rats. In the current work the proximity ligation assay (PLA) was used to further study the A2AR‐D2R heteroreceptor complexes in the nucleus accumbens shell and core as well as the dorsal striatum under the influence of cocaine self‐administration in rats. A significant increase in the A2AR‐D2R PLA positive clusters was observed in the nucleus accumbens shell but not in the other regions vs yoked saline controls using the duolink software. Additionally, cocaine self‐administration evoked a selective and significant increase in the density of D2R‐sigma1R positive clusters in the nucleus accumbens shell vs yoked saline controls, while a significant reduction of the density of the D2R‐sigma1R positive clusters was found in the dorsal part of the dorsal striatum. The results suggest that cocaine self‐administration can reorganize A2AR and D2R into increased A2AR‐D2R heteroreceptor complexes in the nucleus accumbens shell associated with increases in the D2R‐sigma1R heteroreceptor complexes in this region. This reorganization can contribute to the demonstrated anti‐cocaine actions of A2A receptor agonists and the putative formation of A2AR‐D2R‐sigma1R heterocomplexes. HighlightsIncreased A2A‐D2 heterocomplexes in accumbens shell after cocaine self‐administrationIncreased D2‐Sigma1R heterocomplexes in accumbens shell after cocaine self‐administrationReduced D2‐Sigma1R heterocomplexes in caudate putamen after cocaine self‐administrationIncreased A2A‐D2 heterocomplexes may contribute to reducing cocaine reward.