title: Understanding the Functional Plasticity in Neural Networks of the Basal Ganglia in Cocaine Use Disorder: A Role for Allosteric Receptor-Receptor Interactions in A2A-D2 Heteroreceptor Complexes.
abstract: Our hypothesis is that allosteric receptor-receptor interactions in homo- and heteroreceptor complexes may form the molecular basis of learning and memory. This principle is illustrated by showing how cocaine abuse can alter the adenosine A2AR-dopamine D2R heterocomplexes and their receptor-receptor interactions and hereby induce neural plasticity in the basal ganglia. Studies with A2AR ligands using cocaine self-administration procedures indicate that antagonistic allosteric A2AR-D2R heterocomplexes of the ventral striatopallidal GABA antireward pathway play a significant role in reducing cocaine induced reward, motivation, and cocaine seeking. Anticocaine actions of A2AR agonists can also be produced at A2AR homocomplexes in these antireward neurons, actions in which are independent of D2R signaling. At the A2AR-D2R heterocomplex, they are dependent on the strength of the antagonistic allosteric A2AR-D2R interaction and the number of A2AR-D2R and A2AR-D2R-sigma1R heterocomplexes present in the ventral striatopallidal GABA neurons. It involves a differential cocaine-induced increase in sigma1Rs in the ventral versus the dorsal striatum. In contrast, the allosteric brake on the D2R protomer signaling in the A2AR-D2R heterocomplex of the dorsal striatopallidal GABA neurons is lost upon cocaine self-administration. This is potentially due to differences in composition and allosteric plasticity of these complexes versus those in the ventral striatopallidal neurons.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius väg 8. 17177 Stockholm, Sweden; Department of Biomolecular Science, Section of Physiology, University of Urbino, Campus Scientifico Enrico Mattei, Via Ca' le Suore 2, I-61029 Urbino, Italy; Observatorio Cubanos de Neurociencias, Grupo Bohío-Estudio, Yaguajay, Cuba.
authors.forename: Dasiel O
authors.initials: DO
authors.lastname: Borroto-Escuela
authors.affiliation: Laboratory of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, PL-31-343 Kraków, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Wydra
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius väg 8. 17177 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: Universidad de Málaga, Instituto de Investigación Biomédica de Málaga, Facultad de Medicina, Málaga, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Narvaez
authors.affiliation: Observatorio Cubanos de Neurociencias, Grupo Bohío-Estudio, Yaguajay, Cuba; Universidad de Málaga, Instituto de Investigación Biomédica de Málaga, Facultad de Medicina, Málaga, Spain; Centro Nacional de Neurociencias, La Habana, Cuba.
authors.forename: Fidel
authors.initials: F
authors.lastname: Corrales
authors.affiliation: Laboratory of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, PL-31-343 Kraków, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zaniewska
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius väg 8. 17177 Stockholm, Sweden.
authors.forename: Luigi F
authors.initials: LF
authors.lastname: Agnati
authors.affiliation: Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; Centro de Investigaciones en Red, Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Franco
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Tanganelli
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Luca
authors.identifier: 0000-0003-2390-6414
authors.initials: L
authors.lastname: Ferraro
authors.affiliation: Laboratory of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, PL-31-343 Kraków, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Filip
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius väg 8. 17177 Stockholm, Sweden.
authors.forename: Kjell
authors.identifier: 0000-0001-8491-4288
authors.initials: K
authors.lastname: Fuxe
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012646:Self Administration
chemical_list: D058906:Purinergic P1 Receptor Agonists; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D003042:Cocaine