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Trends Pharmacol Sci. 2018 Dec;39(12):1008-1020. doi: 10.1016/j.tips.2018.10.007. Epub 2018 Oct 29.

A2AR-D2R Heteroreceptor Complexes in Cocaine Reward and Addiction.

Author information

1
Department of Neuroscience, Karolinska Institutet, Solnavägen 9, Stockholm, Sweden.
2
Institute of Pharmacology, Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Smetna, Kraków, Poland.
3
Department of Neuroscience, Karolinska Institutet, Solnavägen 9, Stockholm, Sweden. Electronic address: kjell.fuxe@ki.se.

Abstract

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.

KEYWORDS:

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

PMID:
30384981
DOI:
10.1016/j.tips.2018.10.007

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