Adenosine A 2A-Cannabinoid CB 1 Receptor Heteromers in the Hippocampus: Cannabidiol Blunts Δ 9-Tetrahydrocannabinol-Induced Cognitive Impairment

Mol Neurobiol. 2019 Aug;56(8):5382-5391. doi: 10.1007/s12035-018-1456-3. Epub 2019 Jan 4.


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.

MeSH terms

  • Animals
  • Cannabidiol / pharmacology
  • Cannabidiol / therapeutic use*
  • Cognitive Dysfunction / chemically induced*
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / physiopathology
  • Dronabinol / adverse effects*
  • Hippocampus / metabolism*
  • Hippocampus / physiopathology
  • Hippocampus / ultrastructure
  • Locomotion / drug effects
  • Male
  • Mice, Inbred C57BL
  • Presynaptic Terminals / drug effects
  • Presynaptic Terminals / metabolism
  • Protein Multimerization* / drug effects
  • Receptor, Adenosine A2A / metabolism*
  • Receptor, Cannabinoid, CB1 / metabolism*


  • Receptor, Adenosine A2A
  • Receptor, Cannabinoid, CB1
  • Cannabidiol
  • Dronabinol