GPCR heteroreceptor complexes and their receptor-receptor interactions as an emerging target for treatment of cocaine use disorder

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Fuxe K1, Hansson AC2, Wydra K3, Pintsuk J1, Pomierny B1, Barbieri, E1, Li X1, Filip M3, Borroto-Escuela DO1

1Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden 2Institute of Psychopharmacology, CIMH, Mannheim, Germany
3Polish Academy of Sciences, Krakow,Poland

Indications for the existence allosteric receptor-receptor interactions were first obtained in the early 1980ies by the demonstration that neuropeptides could modulate the binding characteristics of subtypes of monoamine receptors in membrane preparations. To-day GPCR heteroreceptor complexes with allosteric receptor-receptor interactions operating over the receptor interfaces are regarded as major integrative centers at the molecular level and their receptor protomers can achieve a number of different functions through the allosteric interactions. Thus, dynamic changes can develop in receptor protomer recognition,signaling and trafficking. Disturbances in these heterocomplexes and in their balance with e.g. corresponding homoreceptor complexes and adapter/scaffolding proteins can contribute to development of schizophrenia and addiction. A major heteroreceptor complex in these two diseases is the A2A-D2 heteroreceptor complex in the ventral striatum with dynamic antagonistic receptor-receptor interactions, mainly present in the ventral striato-pallidal GABA anti-reward system.This system regulates the salience of stimuli. Our findings with A2A agonists support a critical role for A2A receptor activity involving the nucleus accumbens in counteracting the reinforcing and/or motivational properties of cocaine or food rewards and to block cocaine and food relapse. The hypothesis is introduced that the agonist activated A2A protomer significantly contributes to anti-cocaine actions by inhibiting the D2 protomer signaling of the A2A-D2 heteroreceptor complex, increasing activity of the anti-reward system. Cocaine self-administration differentially affects allosteric A2A-D2 receptor-receptor interactions in the ventral vs the dorsal striatum as compared to the corresponding brain regions of yoked saline rats. In the ventral striatum an enhancement of the antagonistic allosteric A2AR-D2R interaction is observed supporting the hypothesis that A2AR agonists can be used to treat cocaine addiction (reward) by inter alia targeting the A2AR protomers of the ventral striatal A2AR-D2R heteroreceptor complexes. In contrast, the antagonistic A2AR-D2-likeR interactions disappeared upon cocaine self-administration in the dorsal striatum which may inter alia contribute to the development of locomotor sensitization and/or habit forming learning. Potential regional differences in the composition and stoichiometry of the A2AR-D2R heteroreceptor complexes can explain this phenomenon induced by cocaine-selfadministration. The question is if the reorganization of the heterocomplexes and their receptor-receptor interactions by cocaine is irreversible or disappears upon cocaine withdrawal?