Opinion
A2AR-D2R Heteroreceptor Complexes in Cocaine Reward and Addiction

https://doi.org/10.1016/j.tips.2018.10.007Get rights and content

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.

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.

Section snippets

Allosteric Receptor–Receptor Interactions in GPCR Homomers and Heteromers

The molecular structure and function of G protein-coupled receptors (GPCRs) was discovered by Nobel Laureates Robert Lefkowitz and Brian Kobilka [1]. Initially, these were regarded to operate as monomers. However, GPCR heteromers (see Glossary) have now been discussed and elucidated by publications for more than two decades 2, 3. In the past few years, their existence has been further established by crystallography, super-resolution imaging, and spatial intensity distribution analysis [4]. A

Formation of Drug Memories in Cocaine Reward and Addiction

Milton and Everitt [10] initially introduced the concept that drug addiction represented a disorder of learning and memory. They proposed that the existence of persistent maladaptive drug memories can be the basis of drug addiction. In this context, our hypothesis on the molecular basis of learning and memory 11, 12 should be mentioned. It states that the dynamic regulation of synaptic and extrasynaptic homo- and heteroreceptor complexes leads to learning or short-term memory and their

Sigma1R-D2R Receptor–Protein Complexes on Exposure to Cocaine

The sigma-1 receptor (Sigma1R) is an intracellular chaperone that has two transmembrane domains and is located at the interface of the endoplasmic reticulum (ER) and the mitochondria 19, 20. Cocaine has the ability to act as a Sigma1R agonist. Upon activation by cocaine, Sigma1R becomes translocated from the ER into the plasma membrane, where it interacts with D1R and D2R and alters their signaling 21, 22. Sigma1R also dynamically interacts with ion channels such as the Kv1.2 channels; this

Changes in Allosteric A2AR-D2R Interactions and A2AR-D2R Heteroreceptor Complexes upon Cocaine Self-Administration

In the sections below, we review the marked changes that develop in the allosteric receptor–receptor interactions of the A2AR-D2R heteroreceptor complexes in the nucleus accumbens upon cocaine self-administration.

Cocaine Reward

To reduce cocaine rewarding properties, the aim is to increase activity in the D2R-positive GABA anti-reward neurons by using A2AR agonists mainly acting at the A2AR protomers of the A2AR-D2R complexes. Brain-penetrant heterobivalent drugs with, for example, A2AR agonist and D2R antagonist pharmacophores can improve treatment by more selective targeting of the A2AR-D2R heteroreceptor complex. The increase in anti-reward (aversion) by these treatments may stop the cocaine use.

Cocaine Addiction

Treatment should,

Concluding Remarks and Future Perspectives

The current research on A2AR-D2R heteroreceptor complexes in the ventral striato-pallidal GABA anti-reward neurons has provided evidence that they play a critical role in cocaine self-administration. Indeed, a reorganization of the A2AR-D2R heteroreceptor complexes with altered antagonistic A2AR-D2R receptor–receptor interactions brings down cocaine reward. This process may lead to an irreversible brake on D2R protomer recognition and signaling in which the Sigma1R also participates. As a

Acknowledgments

This work was supported by the Swedish Medical Research Council (62X-00715-50-3) and Parkinson Fonden to K.F. and by Hjärnfonden (F02018-0286) and Karolinska Institutet Forskningsstiftelser to D.O.B-E. The statutory funds from the Institute of Pharmacology, Polish Academy of Sciences supported the work of K.W. and M.F. D.O.B-E. belongs to the ‘Academia de Biólogos Cubanos’ group.

Glossary

A2AR
the adenosine A2A receptor, a member of the GPCR family, is one of several receptor subtypes for adenosine. It is abundant in the basal ganglia and is a major target of caffeine. The activity of A2AR is mediated by Gs protein that activates adenylyl cyclase. A variety of functional A2AR heteroreceptor complexes have been found in the brain, adding a further degree of complexity to the role of adenosine in modulation of neuronal activity.
Allosteric receptor–receptor interaction
when the

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