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Mol Pharmacol. 2018 Jul;94(1):743-748. doi: 10.1124/mol.118.111864. Epub 2018 Apr 18.

Cannabidiol Inhibits Endocannabinoid Signaling in Autaptic Hippocampal Neurons.

Author information

1
Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana straiker@indiana.edu.
2
Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana.

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.

PMID:
29669714
PMCID:
PMC5988021
[Available on 2019-07-01]
DOI:
10.1124/mol.118.111864
[Indexed for MEDLINE]

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