TY - JOUR
T1 - L-DOPA disrupts adenosine A2A-cannabinoid CB1-dopamine D2 receptor heteromer cross-talk in the striatum of hemiparkinsonian rats
T2 - Biochemical and behavioral studies
AU - Pinna, Annalisa
AU - Bonaventura, Jordi
AU - Farré, Daniel
AU - Sánchez, Marta
AU - Simola, Nicola
AU - Mallol, Josefa
AU - Lluís, Carme
AU - Costa, Giulia
AU - Baqi, Younis
AU - Müller, Christa E.
AU - Cortés, Antoni
AU - McCormick, Peter
AU - Canela, Enric I.
AU - Martínez-Pinilla, Eva
AU - Lanciego, José L.
AU - Casadó, Vicent
AU - Armentero, Marie Therese
AU - Franco, Rafael
N1 - Funding Information:
We thank Jasmina Jiménez (Molecular Neurobiology laboratory, Barcelona University) for her technical assistance. This study was supported by grants from Spanish Ministerio de Ciencia y Tecnología (SAF2012-39875-C01-01, SAF2010-18472, and SAF2008-03118-E, within the framework of the Era-NET Neuron program), a grant ( RC2008MinSal/Era-NET ) from the Italian Ministry of Health in the frame of the Era-NET NEURON program and a grant for collaborative projects ( PI2011/02-7 ) from the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) . PJM is a Ramón y Cajal Fellow. Y.B. and C.E.M. were funded by the BMBF, Germany (01EW0911) in the frame of Era-NET NEURON program. Dr. Nicola Simola gratefully acknowledges Sardinia Regional Government for the financial support (P.O.R. Sardegna F.S.E. Operational Programme of the Autonomous Region of Sardinia, European Social Fund 2007–2013 — Axis IV Human Resources, Objective l.3, Line of Activity l.3.1 “Avviso di chiamata per il finanziamento di Assegni di Ricerca”).
PY - 2014/3
Y1 - 2014/3
N2 - 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.
AB - 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.
KW - A antagonists
KW - Behavior
KW - CB antagonists
KW - G-protein-coupled receptors
KW - L-DOPA
KW - Parkinson's disease
KW - Radioligand binding
UR - http://www.scopus.com/inward/record.url?scp=84892840403&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84892840403&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2013.12.021
DO - 10.1016/j.expneurol.2013.12.021
M3 - Article
C2 - 24412491
AN - SCOPUS:84892840403
SN - 0014-4886
VL - 253
SP - 180
EP - 191
JO - Experimental Neurology
JF - Experimental Neurology
ER -