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Mol Neurobiol. 2019 Jan 4. doi: 10.1007/s12035-018-1456-3. [Epub ahead of print]

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

Author information

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.
2
Universitat de Barcelona, Institut de Neurociències, Barcelona, Spain.
3
Department of Anatomy, Hokkaido University School of Medicine, Sapporo, Japan.
4
CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Madrid, Spain.
5
Unitat de Anatomia Patològica, Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
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.
7
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. fciruela@ub.edu.
8
Universitat de Barcelona, Institut de Neurociències, Barcelona, Spain. fciruela@ub.edu.

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.

KEYWORDS:

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

PMID:
30610611
DOI:
10.1007/s12035-018-1456-3

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