A2AR-D2R Heteroreceptor Complexes in Cocaine Reward and Addiction. (December 2018)

• Record Type: Journal Article
• Authors: Borroto-Escuela, Dasiel O.; Wydra, Karolina; Filip, Malgorzata; Fuxe, Kjell
• Is Part Of: Trends in pharmacological sciences. Volume 39:Number 12(2018)
• Page Start: 1008
• Page End: 1020
• Publication Date: 2018-12
• Subjects: heteroreceptor complexes -- receptor–receptor interactions -- cocaine self-administration -- addiction -- long-term memory; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2018.10.007
• Languages: English
• ISSNs: 0165-6147

Abstract

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. Highlights: Cocaine can induce pathological A2AR-D2R-Sigma1R complexes in nucleus accumbens. These A2AR-D2R-Sigma1R complexes can put a brake on D2R signaling. These pathological A2AR-D2R-Sigma1R complexes are proposed to produce cocaine addiction. Future pharmacotherapy should target accumbal pathological A2AR-D2R-Sigma1R complexes by using interface-interfering peptides and heterobivalent compounds.