L-DOPA-treatment in primates disrupts the expression of A(2A) adenosine-CB(1) cannabinoid-D(2) dopamine receptor heteromers in the caudate nucleus.
The molecular basis of priming for L-DOPA-induced dyskinesias in Parkinson's disease (PD), which depends on the indirect pathway of motor control, is not known. In rodents, the indirect pathway contains striatopallidal GABAergic neurons that express heterotrimers composed of A(2A) adenosine, CB(1) cannabinoid and D(2) dopamine receptors that regulate dopaminergic neurotransmission. The present study was designed to investigate the expression of these heteromers in the striatum of a primate model of Parkinson's disease and to determine whether their expression and pharmacological properties are altered upon L-DOPA treatment. By using the recently developed in situ proximity ligation assay and by identification of a biochemical fingerprint, we discovered a regional distribution of A(2A)/CB(1) /D(2) receptor heteromers that predicts differential D(2)-mediated neurotransmission in the caudate-putamen of Macaca fascicularis. Whereas heteromers were abundant in the caudate nucleus of both naïve and MPTP-treated monkeys, L-DOPA treatment blunted the biochemical fingerprint and led to weak heteromer expression. These findings constitute the first evidence of altered receptor heteromer expression in pathological conditions and suggest that drugs targeting A(2A)-CB(1) -D(2) receptor heteromers may be successful to either normalize basal ganglia output or prevent L-DOPA-induced side effects.
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.
Jordi
J
Bonaventura
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain; Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain.
Alberto J
AJ
Rico
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.
Estefanía
E
Moreno
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain; Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain.
Salvador
S
Sierra
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.
Marta
M
Sánchez
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain; Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain.
Natasha
N
Luquin
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.
Daniel
D
Farré
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Germany.
Christa E
CE
Müller
Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain.
Eva
E
Martínez-Pinilla
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.
Antoni
A
Cortés
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.
Josefa
J
Mallol
Laboratory of Functional Neurochemistry, C. Mondino National Neurological Institute, via Mondino 2, Pavia, Italy.
Marie-Therese
MT
Armentero
CNR Institute of Neuroscience, Cagliari, Italy.
Annalisa
A
Pinna
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.
Enric I
EI
Canela
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.
Carme
C
Lluís
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.
Peter J
PJ
McCormick
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain; Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain.
José L
JL
Lanciego
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. Electronic address: vcasado@ub.edu.
Vicent
V
Casadó
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. Electronic address: rfranco@ub.edu.
Rafael
R
Franco
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D002421:Caudate Nucleus / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D007980:Levodopa / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D043884:Receptor, Cannabinoid, CB1; D017448:Receptors, Dopamine D2; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine
Caudate; Dopamine; Parkinson's disease; Putamen; Receptor heteromer; Striatum; l-Dopa