title: Cocaine self-administration differentially affects allosteric A2A-D2 receptor-receptor interactions in the striatum. Relevance for cocaine use disorder.
abstract: In the current study behavioral and biochemical experiments were performed to study changes in the allosteric A2AR-D2R interactions in the ventral and dorsal striatum after cocaine self-administration versus corresponding yoked saline control. By using ex vivo [(3)H]-raclopride/quinpirole competition experiments, the effects of the A2AR agonist CGS 21680 (100 nM) on the KiH and KiL values of the D2-like receptor (D2-likeR) were determined. One major result was a significant reduction in the D2-likeR agonist high affinity state observed with CGS 21680 after cocaine self-administration in the ventral striatum compared with the yoked saline group. The results therefore support the hypothesis that A2AR agonists can at least in part counteract the motivational actions of cocaine. This action is mediated via the D2-likeR by targeting the A2AR protomer of A2AR-D2-like R heteroreceptor complexes in the ventral striatum, which leads to the reduction of D2-likeR protomer recognition through the allosteric receptor-receptor interaction. In contrast, in the dorsal striatum the CGS 21680-induced antagonistic modulation in the D2-likeR agonist high affinity state was abolished after cocaine self-administration versus the yoked saline group probably due to a local dysfunction/disruption of the A2AR-D2-like R heteroreceptor complexes. Such a change in the dorsal striatum in cocaine self-administration can contribute to the development of either locomotor sensitization, habit-forming learning and/or the compulsive drug seeking by enhanced D2-likeR protomer signaling. Potential differences in the composition and stoichiometry of the A2AR-D2R heteroreceptor complexes, including differential recruitment of sigma 1 receptor, in the ventral and dorsal striatum may explain the differential regional changes observed in the A2A-D2-likeR interactions after cocaine self-administration.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Biomedicine and Translational Medicine, Department of Physiology, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia. Electronic address: juliaofli@gmail.com.
authors.forename: Julia
authors.initials: J
authors.lastname: Pintsuk
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Earth, Life and Environmental Sciences, Section of Physiology, Campus Scientifico Enrico Mattei, via Ca' le Suore 2, I-61029 Urbino, Italy. Electronic address: Dasiel.BorrotoEscuela@ki.se.
authors.forename: Dasiel O
authors.initials: DO
authors.lastname: Borroto-Escuela
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: bartosz.pomierny@uj.edu.pl.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Pomierny
authors.affiliation: Laboratory of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, PL-31-343, Kraków, Poland. Electronic address: wydra@if-pan.krakow.pl.
authors.forename: Karolina
authors.initials: K
authors.lastname: Wydra
authors.affiliation: Laboratory of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, PL-31-343, Kraków, Poland. Electronic address: Zaniew@if-pan.krakow.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zaniewska
authors.affiliation: Laboratory of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, PL-31-343, Kraków, Poland. Electronic address: mal.fil@if-pan.krakow.pl.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Filip
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: Kjell.Fuxe@ki.se.
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D008297:Male; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012646:Self Administration
chemical_list: D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D003042:Cocaine
keywords: Addiction; Adenosine A2A receptor; Allosteric receptor-receptor interactions; Cocaine self-administration; Dopamine D2 receptor; Heteroreceptor complex