title: Cocaine self-administration specifically increases A2AR-D2R and D2R-sigma1R heteroreceptor complexes in the rat nucleus accumbens shell. Relevance for cocaine use disorder.
abstract: Adenosine 2A receptor (A2AR) agonists were indicated to reduce cocaine reward and cocaine seeking mainly through activation of antagonistic allosteric A2AR-dopamine D2R (D2R) interactions in A2AR-D2R heteroreceptor complexes. Furthermore, it was shown that modulation of cocaine reward involves antagonistic A2AR-D2R interactions in the ventral but not the dorsal striatum in rats. In the current work the proximity ligation assay (PLA) was used to further study the A2AR-D2R heteroreceptor complexes in the nucleus accumbens shell and core as well as the dorsal striatum under the influence of cocaine self-administration in rats. A significant increase in the A2AR-D2R PLA positive clusters was observed in the nucleus accumbens shell but not in the other regions vs yoked saline controls using the duolink software. Additionally, cocaine self-administration evoked a selective and significant increase in the density of D2R-sigma1R positive clusters in the nucleus accumbens shell vs yoked saline controls, while a significant reduction of the density of the D2R-sigma1R positive clusters was found in the dorsal part of the dorsal striatum. The results suggest that cocaine self-administration can reorganize A2AR and D2R into increased A2AR-D2R heteroreceptor complexes in the nucleus accumbens shell associated with increases in the D2R-sigma1R heteroreceptor complexes in this region. This reorganization can contribute to the demonstrated anti-cocaine actions of A2A receptor agonists and the putative formation of A2AR-D2R-sigma1R heterocomplexes.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden; Department of Earth, Life and Environmental Sciences, Section of Physiology, Campus Scientifico Enrico Mattei, University of Urbino, via Ca' le Suore 2, I-61029 Urbino, Italy; Observatorio Cubano de Neurociencias, Grupo Bohío-Estudio, Zayas 50, 62100 Yaguajay, Cuba. Electronic address: Dasiel.Borroto-Escuela@ki.se.
authors.forename: Dasiel O
authors.initials: DO
authors.lastname: Borroto-Escuela
authors.affiliation: Universidad de Málaga, Instituto de Investigación Biomédica de Málaga, Facultad de Medicina, Campus de Teatinos s/n, 29071 Málaga, Spain. Electronic address: mnarvaez@uma.es.
authors.forename: Manuel
authors.initials: M
authors.lastname: Narváez
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, Laboratory of Drug Addiction Pharmacology, Smetna, PL-31-343 Kraków, Poland. Electronic address: wydra@if-pan.krakow.pl.
authors.forename: Karolina
authors.initials: K
authors.lastname: Wydra
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden; Institute of Biomedicine and Translational Medicine, Department of Physiology, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia.
authors.forename: Julia
authors.initials: J
authors.lastname: Pintsuk
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden.
authors.forename: Luca
authors.initials: L
authors.lastname: Pinton
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Von Eulers väg 8, 171 77 Stockholm, Sweden. Electronic address: tony.jimenez-beristain@ki.se.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimenez-Beristain
authors.affiliation: Department of Earth, Life and Environmental Sciences, Section of Physiology, Campus Scientifico Enrico Mattei, University of Urbino, via Ca' le Suore 2, I-61029 Urbino, Italy. Electronic address: michael.dipalma@uniurb.it.
authors.forename: Michael
authors.initials: M
authors.lastname: Di Palma
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, Laboratory of Drug Addiction Pharmacology, Smetna, PL-31-343 Kraków, Poland. Electronic address: czyzyk@if-pan.krakow.pl.
authors.forename: Joanna
authors.initials: J
authors.lastname: Jastrzębska
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, Laboratory of Drug Addiction Pharmacology, Smetna, 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, Retzius väg 8, 171 77 Stockholm, Sweden. Electronic address: Kjell.Fuxe@ki.se.
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D012646:Self Administration
chemical_list: D043705:Receptor, Adenosine A2A; D003042:Cocaine
keywords: Adenosine A2A receptor; Cocaine self-administration; Dopamine D2 receptor; Heteroreceptor complexes; Sigma 1 receptor; Substance use disorder