Cannabidiol Inhibits Endocannabinoid Signaling in Autaptic Hippocampal Neurons

Δ⁹-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two main cannabinoid constituents of marijuana and hashish. The pharmacology of Δ⁹-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 Δ⁹-THC–induced effects. It was established early on that CBD binds poorly to the orthosteric site of CB₁ or CB₂ cannabinoid receptors, and its actions were commonly attributed to other noncannabinoid receptor mechanisms. However, recent evidence suggests that CBD does indeed act at cannabinoid CB₁ receptors as a negative allosteric modulator (NAM) of CB₁ 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 CB₁ 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.