title: L-DOPA disrupts adenosine A(2A)-cannabinoid CB(1)-dopamine D(2) receptor heteromer cross-talk in the striatum of hemiparkinsonian rats: biochemical and behavioral studies.
abstract: Long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA), still the most effective treatment in Parkinson's disease (PD), is associated with severe motor complications such as dyskinesia. Experimental and clinical data have indicated that adenosine A2A receptor antagonists can provide symptomatic improvement by potentiating L-DOPA efficacy and minimizing its side effects. It is known that the G-protein-coupled adenosine A2A, cannabinoid CB1 and dopamine D2 receptors may interact and form functional A2A-CB1-D2 receptor heteromers in co-transfected cells as well as in rat striatum. These data suggest that treatment with a combination of drugs or a single compound selectively acting on A2A-CB1-D2 heteromers may represent an alternative therapeutic treatment of PD. We investigated the expression of A2A-CB1-D2 receptor heteromers in the striatum of both naïve and hemiparkinsonian rats (HPD-rats) bearing a unilateral 6-hydroxydopamine (6-OHDA) lesion, and assessed how receptor heteromer expression and biochemical properties were affected by L-DOPA treatment. Radioligand binding data showed that A2A-CB1-D2 receptor heteromers are present in the striatum of both naïve and HPD-rats. However, behavioral results indicated that the combined administration of A2A (MSX-3 or SCH58261) and CB1 (rimonabant) receptor antagonists, in the presence of L-DOPA does not produce a response different from administration of the A2A receptor antagonist alone. These behavioral results prompted identification of heteromers in L-DOPA-treated animals. Interestingly, the radioligand binding results in samples from lesioned animals suggest that the heteromer is lost following acute or chronic treatment with L-DOPA.
authors.affiliation: National Research Council of Italy (CNR), Institute of Neuroscience-Cagliari, 09124 Cagliari, Italy. Electronic address: apinna@unica.it.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pinna
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Bonaventura
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Farré
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Sánchez
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, 09124 Cagliari, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Simola
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain.
authors.forename: Josefa
authors.initials: J
authors.lastname: Mallol
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain.
authors.forename: Carme
authors.initials: C
authors.lastname: Lluís
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, 09124 Cagliari, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Costa
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Germany.
authors.forename: Younis
authors.initials: Y
authors.lastname: Baqi
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Germany.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Cortés
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain.
authors.forename: Peter
authors.initials: P
authors.lastname: McCormick
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain.
authors.forename: Enric I
authors.initials: EI
authors.lastname: Canela
authors.affiliation: Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Martínez-Pinilla
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain; Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Lanciego
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain.
authors.forename: Vicent
authors.initials: V
authors.lastname: Casadó
authors.affiliation: Laboratory of Functional Neurochemistry, C. Mondino National Neurological Institute, via Mondino 2, Pavia, Italy.
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Armentero
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain; Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Franco
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007839:Functional Laterality / Q000187:drug effects* / Q000502:physiology; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D010880:Piperidines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D000077285:Rimonabant; D013619:Tacrine / Q000633:toxicity; D013997:Time Factors; D014202:Tremor / Q000139:chemically induced
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D063387:Cannabinoid Receptor Antagonists; D002800:Cholinesterase Inhibitors; D015259:Dopamine Agents; D010880:Piperidines; D011720:Pyrazoles; D007980:Levodopa; D013619:Tacrine; D016627:Oxidopamine; D000077285:Rimonabant
keywords: A(2A) antagonists; Behavior; CB(1) antagonists; G-protein-coupled receptors; Parkinson's disease; Radioligand binding; l-DOPA