Cannabidiol Inhibits Endocannabinoid Signaling in Autaptic Hippocampal Neurons

Abstract

Δ-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two main cannabinoid constituents of marijuana and hashish. The pharmacology of Δ-THC has been extensively studied, whereas our understanding of the pharmacology of CBD has remained limited, despite excitement in CBD's potential role in treating certain pediatric epilepsies and its reputation for attenuating some Δ-THC-induced effects. It was established early on that CBD binds poorly to the orthosteric site of CB or CB cannabinoid receptors, and its actions were commonly attributed to other noncannabinoid receptor mechanisms. However, recent evidence suggests that CBD does indeed act at cannabinoid CB receptors as a negative allosteric modulator (NAM) of CB signaling. By altering the orthosteric signaling of a G protein-coupled receptor, allosteric modulators greatly increase the richness of G protein-coupled receptor pharmacology. We have recently surveyed candidate CB NAMs in autaptic hippocampal neurons, a well-characterized neuronal model of endogenous cannabinoid signaling, and have now tested CBD in this model. We find that although CBD has no direct effect on excitatory transmission, it does inhibit two forms of endogenous cannabinoid-mediated retrograde synaptic plasticity: depolarization-induced suppression of excitation and metabotropic suppression of excitation, while not affecting signaling via GABA-B receptors. These results are consistent with the recently described NAM activity of CBD and suggest interesting possible mechanisms for CBD's therapeutic actions.

Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol‐dimethylheptyl at the type 1 and type 2 cannabinoid receptors

“…CBD reduced [ 3 H]‐CP55,940 binding with an apparent K i much lower than the affinity estimated in signalling assays, indicating reduced orthosteric ligand binding above 3 μM CBD and affirming higher affinity NAM signalling activity (Smith et al ., ; Hudson et al ., ; Congreve et al ., ). We observed here, and previously (Laprairie et al ., ), that CBD functioned as a NAM in several cell culture assays at concentrations lower than the reported concentrations at which CBD acts an orthosteric ligand of the CB 1 receptor (Thomas et al ., ; Hayakawa et al ., ; McPartland et al ., ; Sabatucci et al ., ; Straiker et al ., ). In contrast, CBD‐DMH may enhance the binding of the orthosteric probe to a maximum and, at higher concentrations, reduce orthosteric probe binding, producing a bell‐shaped curve.…”

“…() recently confirmed the importance of the CB 1 receptor N‐ terminus for allosteric ligands – including CBD – in silico , and our findings here support their modelling. Further, the NAM activity of CBD was expanded upon in an autaptic hippocampal neuron model, suggesting it may play a role in depolarization‐induced suppression of excitation (Straiker et al ., ). For the CB 2 receptor, it remains unknown whether the N ‐terminus affects ligand activity or binding (El Bakali et al ., ).…”

“…Based on these data, we propose that CBD has high affinity for an allosteric site in the outer vestibule of the CB 1 receptor in the inactive conformation. This hypothesis is supported by our earlier mutagenesis work with CB 1 receptors (Laprairie et al ., ), recent modelling of CB 1 receptor 5TGZ with CBD (Sabatucci et al ., ), electrophysiology data from cultural autaptic hippocampal neurons (Straiker et al, ) and accumulating data showing the class A GPCR outer vestibule to be a common binding region for allosteric modulators (Congreve et al ., ).…”

“…CBD can also act as a PAM of the opioid μ‐ and δ‐receptors (Kathmann et al ., ). Importantly, CBD can mediate NAM and antagonistic effects at CB 1 receptors at concentrations well below the reported affinity ( K i ) values of CBD at the orthosteric site of CB 1 receptors, suggesting that a high affinity CBD binding site, distinct from the orthosteric site on CB 1 receptors, exists (Pertwee et al ., ; Thomas et al ., ; Hayakawa et al ., ; Laprairie et al ., ; McPartland et al ., ; Sabatucci et al ., ; Straiker et al ., ). Given the diverse range of activities of CBD, modified synthetic CBD derivatives were synthesized as tools to elucidate the structure–activity relationship of CBD at CB 1 and CB 2 receptors.…”

What is currently known about cannabidiol and ocular pressure

“…The mechanism by which CBD raises ocular pressure is likely through antagonism of the CB1 receptors. THC activates CB1 receptors to lower pressure but CBD has been reported to act as a negative allosteric modulator of CB1 signaling [21][22][23]. Allosteric modulators differ from classical 'orthosteric' ligands in that they act at a secondary site to modulate the signaling of the receptor.…”