Cannabidiol Inhibits Endocannabinoid Signaling in Autaptic Hippocampal Neurons

Abstract

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.

Fig. 1.

CBD suppresses CB₁ receptor–mediated DSE. (A) CBD (500 nM) does not directly inhibit excitatory postsynaptic currents. (B) The 100 or 500 nM CBD treatment (5 minutes) shifts the response curve for DSE in a concentration-dependent manner. Inset shows sample EPSCs before and after DSE under baseline conditions (top) and after CBD (500 nM) treatment (bottom). (C) Sample time course showing DSE responses to progressively longer depolarizations before and after 100 nM CBD treatment. (D) Averaged DSE time course in response to 3-second depolarization before and after 500 nM CBD treatment. (E) Representative experiment showing that half-maximal 2-AG responses (500 nM) are diminished by 500 nM CBD. (F) Inhibition by 2-AG (500 nM) alone gives a stronger response than in the presence of CBD (500 nM). (G) Representative experiment showing that GABA-B responses (25 μM baclofen) are unaltered by 500 nM CBD treatment. (H) Inhibition of EPSCs by baclofen alone or in combination with CBD (500 nM). *P < 0.05 by paired t test.

Fig. 2.

CBD suppresses endogenous CB₁ receptor–mediated metabotropic suppression of excitation. (A) mGluR group I agonist DHPG (10 μM) suppresses EPSCs, but this is reversed by treatment with 500 nM CBD. (B) Sample time course showing DHPG response reversed by subsequent cotreatment with CBD. (C) Bar graph shows maximal inhibition due to DSE before CBD and the effect of DHPG (10 μM) when applied after/with CBD (500 nM). (D) Sample time course showing CBD treatment, followed by coapplication of CBD and DHPG. *P < 0.05 by paired t test.