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Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Hippocampus: Cannabidiol Blunts Δ9-Tetrahydrocannabinol-Induced Cognitive Impairment

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Abstract

At present, clinical interest in the plant-derived cannabinoid compound cannabidiol (CBD) is rising exponentially, since it displays multiple therapeutic properties. In addition, CBD can counteract the undesirable effects of the psychoactive cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) that hinder clinical development of cannabis-based therapies. Despite this attention, the mechanisms of CBD action and its interaction with Δ9-THC are still not completely elucidated. Here, by combining in vivo and complementary molecular techniques, we demonstrate for the first time that CBD blunts the Δ9-THC-induced cognitive impairment in an adenosine A2A receptor (A2AR)-dependent manner. Furthermore, we reveal the existence of A2AR and cannabinoid CB1 receptor (CB1R) heteromers at the presynaptic level in CA1 neurons in the hippocampus. Interestingly, our findings support a brain region-dependent A2AR-CB1R functional interplay; indeed, CBD was not capable of modifying motor functions presumably regulated by striatal A2AR/CB1R complexes, nor anxiety responses related to other brain regions. Overall, these data provide new evidence regarding the mechanisms of action of CBD and the nature of A2AR-CB1R interactions in the brain.

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Acknowledgments

We thank J.A. López-Salcedo for customising the Matlab application for locomotor activity analysis and Esther Castaño and Benjamín Torrejón from the Scientific and Technical Services (CCiT) at the Bellvitge Campus of the University of Barcelona, for their technical assistance.

Funding

The authors’ work was supported by grants from CIBERNED and the Instituto de Salud Carlos III, and co-funded by the FEDER/European Regional Development Fund (ERDF)-a way to build Europe (PIE14/00034 and PI14/00757 to IF). This work was also supported by grants from MINECO-AEI/FEDER, UE (SAF2017-87349-R), the Catalan government (2017 SGR 1604), Fundació la Marató de TV3 (Grant 20152031), FWO (SBO-140028) (Francisco Ciruela) and the MINECO grant BFU2015-63769-R (Rafael Luján).

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Author notes

  1. Ester Aso and Víctor Fernández-Dueñas contributed equally to this work.

Authors and Affiliations

  1. Unitat de Farmacologia, Departament de Patologia i Terapèutica Experimental, Facultat de Medicina i Ciències de la Salut, IDIBELL-Universitat de Barcelona, C/Feixa Llarga s/n, 08907, L’Hospitalet de Llobregat, Spain

    Ester Aso, Víctor Fernández-Dueñas, Marc López-Cano, Jaume Taura & Francisco Ciruela

  2. Universitat de Barcelona, Institut de Neurociències, Barcelona, Spain

    Ester Aso, Víctor Fernández-Dueñas, Marc López-Cano, Jaume Taura, Isidre Ferrer & Francisco Ciruela

  3. Department of Anatomy, Hokkaido University School of Medicine, Sapporo, Japan

    Masahiko Watanabe

  4. CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Madrid, Spain

    Isidre Ferrer

  5. Unitat de Anatomia Patològica, Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL-Universitat de Barcelona, L’Hospitalet de Llobregat, Spain

    Isidre Ferrer

  6. Synaptic Structure Laboratory, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, Campus Biosanitario, Albacete, Spain

    Rafael Luján

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  1. Ester Aso
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Correspondence to Francisco Ciruela.

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The University of Barcelona Committee on Animal Use and Care approved the protocol. Animals were housed and tested in compliance with the guidelines provided by the Guide for the Care and Use of Laboratory Animals [24] and following the European Union directives (2010/63/EU). All efforts were made to minimise animal suffering and the number of animals used.

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Aso, E., Fernández-Dueñas, V., López-Cano, M. et al. Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Hippocampus: Cannabidiol Blunts Δ9-Tetrahydrocannabinol-Induced Cognitive Impairment. Mol Neurobiol 56, 5382–5391 (2019). https://doi.org/10.1007/s12035-018-1456-3

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