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

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 Δ-tetrahydrocannabinol (Δ-THC) that hinder clinical development of cannabis-based therapies. Despite this attention, the mechanisms of CBD action and its interaction with Δ-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 Δ-THC-induced cognitive impairment in an adenosine A receptor (AR)-dependent manner. Furthermore, we reveal the existence of AR and cannabinoid CB receptor (CBR) heteromers at the presynaptic level in CA1 neurons in the hippocampus. Interestingly, our findings support a brain region-dependent AR-CBR functional interplay; indeed, CBD was not capable of modifying motor functions presumably regulated by striatal AR/CBR 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 AR-CBR interactions in the brain.