A2AR-D2R Heteroreceptor Complexes in Cocaine Reward and Addiction

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


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cocaine / pharmacology*
  • Cocaine-Related Disorders / metabolism*
  • Cocaine-Related Disorders / physiopathology
  • Humans
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Receptor, Adenosine A2A / metabolism*
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, sigma / metabolism
  • Reward*


  • Receptor, Adenosine A2A
  • Receptors, Dopamine D2
  • Receptors, sigma
  • sigma-1 receptor
  • Cocaine