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Neuropsychopharmacology. 2018 Apr;43(5):964-977. doi: 10.1038/npp.2017.12. Epub 2017 Jan 19.

Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal Striatum.

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Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.
Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.
Instituto Universitario de Investigación Neuroquímica and Department of Biochemistry and Molecular Biology I, Complutense University, Madrid, Spain.
Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, UK.
School of Biological and Chemical Sciences, Queen Mary, University of London, London, UK.
Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa, Spain.
Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.
Biomedical Science Department, School of Medicine; Institut d'Investigacions Biomèdiques August Pi i Sunyer, and Neuroscience Institute, Barcelona University, Barcelona, Spain.
Pharmacology Unit, Department of Pathology and Experimental Therapeutics, IDIBELL, and Neuroscience Institute, Barcelona University, Barcelona, Spain.
Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK.


The dorsal striatum is a key node for many neurobiological processes such as motor activity, cognitive functions, and affective processes. The proper functioning of striatal neurons relies critically on metabotropic receptors. Specifically, the main adenosine and endocannabinoid receptors present in the striatum, ie, adenosine A2A receptor (A2AR) and cannabinoid CB1 receptor (CB1R), are of pivotal importance in the control of neuronal excitability. Facilitatory and inhibitory functional interactions between striatal A2AR and CB1R have been reported, and evidence supports that this cross-talk may rely, at least in part, on the formation of A2AR-CB1R heteromeric complexes. However, the specific location and properties of these heteromers have remained largely unknown. Here, by using techniques that allowed a precise visualization of the heteromers in situ in combination with sophisticated genetically modified animal models, together with biochemical and pharmacological approaches, we provide a high-resolution expression map and a detailed functional characterization of A2AR-CB1R heteromers in the dorsal striatum. Specifically, our data unveil that the A2AR-CB1R heteromer (i) is essentially absent from corticostriatal projections and striatonigral neurons, and, instead, is largely present in striatopallidal neurons, (ii) displays a striking G protein-coupled signaling profile, where co-stimulation of both receptors leads to strongly reduced downstream signaling, and (iii) undergoes an unprecedented dysfunction in Huntington's disease, an archetypal disease that affects striatal neurons. Altogether, our findings may open a new conceptual framework to understand the role of coordinated adenosine-endocannabinoid signaling in the indirect striatal pathway, which may be relevant in motor function and neurodegenerative diseases.

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