Molecular Neurobiology

, Volume 56, Issue 8, pp 5382–5391 | Cite as

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

  • Ester Aso
  • Víctor Fernández-Dueñas
  • Marc López-Cano
  • Jaume Taura
  • Masahiko Watanabe
  • Isidre Ferrer
  • Rafael Luján
  • Francisco CiruelaEmail author


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.


Cannabidiol Δ9-Tetrahydrocannabinol Cannabis Memory Adenosine 2A receptor Cannabinoid 1 receptor 



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.


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).

Compliance with Ethical Standards

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.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_1456_MOESM1_ESM.xls (34 kb)
Table S1 (XLS 34 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Unitat de Farmacologia, Departament de Patologia i Terapèutica Experimental, Facultat de Medicina i Ciències de la SalutIDIBELL-Universitat de BarcelonaL’Hospitalet de LlobregatSpain
  2. 2.Universitat de BarcelonaInstitut de NeurociènciesBarcelonaSpain
  3. 3.Department of AnatomyHokkaido University School of MedicineSapporoJapan
  4. 4.CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades NeurodegenerativasInstituto Carlos IIIMadridSpain
  5. 5.Unitat de Anatomia Patològica, Departament de Patologia i Terapèutica Experimental, Facultat de MedicinaIDIBELL-Universitat de BarcelonaL’Hospitalet de LlobregatSpain
  6. 6.Synaptic Structure Laboratory, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Departamento de Ciencias Médicas, Facultad de MedicinaUniversidad Castilla-La ManchaAlbaceteSpain

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