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

Abstract

At present, the clinical interest on the plant-derived cannabinoid compound cannabidiol (CBD) is exponentially rising, since it displays multiple therapeutic properties. In addition, CBD can counteract the undesirable effects of the psychoactive cannabinoid Δ⁹-tetrahydrocannabinol (Δ⁹-THC) that dampen the clinical development of cannabisbased therapies. Despite this attention, the CBD mechanism of action and its interaction with Δ⁹-THC are still not completely elucidated. Here, by combining in vivo and molecular complementary 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 revealed the existence of A2AR and cannabinoid CB1 receptor (CB1R) heteromers at the pre-synaptic level in CA1 neurons of the hippocampus. Interestingly, our findings supported a brain region-dependent A2AR-CB1R functional interplay, indeed CBD was not able to modify motor functions presumably regulated by striatal A2AR/CB1R complexes, or anxiety responses related to other brain regions. Overall, these data provide new evidences about the mechanisms of action of CBD and the nature of A2AR-CB1R interaction in brain.

A time‐dependent contribution of hippocampal CB1, CB2 and PPARγ receptors to cannabidiol‐induced disruption of fear memory consolidation

“…Importantly, unlike the present study, in the work by Aso et al (2019), all the drugs were systemically injected, and the antagonists were administered before memory acquisition. Consequently, interference with this memory phase cannot be excludedt.…”

Antioxidative and Anti-Inflammatory Properties of Cannabidiol

“…This suggests that CBD prevents oxidative stress by activating A 2A receptors. It was also shown that A 2A receptors can form heteromers with CB1 receptors in CA1 neurons and in the hippocampus of C57BL/6J mice [112]. Therefore, CBD can modify the functioning of the entire heteromer, and thus modulate the activation of two groups of receptors involved in the regulation of redox balance and inflammation.…”

Neuroprotection Following Concussion: The Potential Role for Cannabidiol

“…100 Indeed, CBD was shown to downregulate inflammatory biomarkers and attenuate microglia activation in a viral mouse model of multiple sclerosis by interacting with A2a receptors. 99 Finally, it was suggested that CBD can blunt the THC-induced cognitive and memory impairments in an A2a receptor-dependent manner, 109 as shown by A2a receptor knockout mice performance in a two-object recognition test. 109 CBD is also known to act directly upon the 5-HT 1A receptor, which is found in the brain in large concentrations, with large densities at the prefrontal cortex, hippocampus, and amygdala.…”

“…99 Finally, it was suggested that CBD can blunt the THC-induced cognitive and memory impairments in an A2a receptor-dependent manner, 109 as shown by A2a receptor knockout mice performance in a two-object recognition test. 109 CBD is also known to act directly upon the 5-HT 1A receptor, which is found in the brain in large concentrations, with large densities at the prefrontal cortex, hippocampus, and amygdala. 110,111 CBD has been shown to exhibit a high potency for this receptor and serves as an agonist, to further stimulate the receptor's properties of decreasing anxiety, pain, and headaches.…”