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 A_2A receptor (A_2AR)-dependent manner. Furthermore, we reveal the existence of A_2AR and cannabinoid CB₁ receptor (CB₁R) heteromers at the presynaptic level in CA1 neurons in the hippocampus. Interestingly, our findings support a brain region-dependent A_2AR-CB₁R functional interplay; indeed, CBD was not capable of modifying motor functions presumably regulated by striatal A_2AR/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 A_2AR-CB₁R interactions in the brain.