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Trends Pharmacol Sci. 2018 Dec;39(12):1008-1020. doi: 10.1016/ Epub 2018 Oct 29.

A2AR-D2R Heteroreceptor Complexes in Cocaine Reward and Addiction.

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Department of Neuroscience, Karolinska Institutet, Solnavägen 9, Stockholm, Sweden.
Institute of Pharmacology, Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Smetna, Kraków, Poland.
Department of Neuroscience, Karolinska Institutet, Solnavägen 9, Stockholm, Sweden. Electronic address:


The concept of allosteric receptor-receptor interactions in G protein-coupled receptor homo- and heteroreceptor complexes in which they physically interact provides a new dimension to molecular integration in the brain. The receptor-receptor interactions dynamically change recognition, pharmacology, signaling, and trafficking of the participating receptors. Among the receptor complexes, disruption of the A2A receptor-dopamine D2 receptor (A2AR-D2R) complex by an A2AR agonist has been shown to fully block the inhibition of cocaine self-administration. Cocaine induced pathological A2AR-D2R-Sigma1R complexes may form a long-term memory with a strong and permanent D2R brake, leading to cocaine addiction. These heteroreceptor complexes can potentially be targeted for future pharmacotherapy of cocaine addiction by using heterobivalent compounds or A2AR-D2R receptor interface-interfering peptides that disrupt the A2AR-D2R-Sigma1R complexes.


addiction; cocaine self-administration; heteroreceptor complexes; long-term memory; receptor–receptor interactions


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