title: The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAAreceptors.
abstract: Cannabidiol (CBD) is a major non-intoxicating component of cannabis and possesses anti-epileptic, anxiolytic and anti-hyperalgesic properties. The mechanism of action of CBD in producing such effects remains unclear. Despite evidence that some endogenous and synthetic cannabinoids interact with GABAAreceptors, no-one has yet investigated the effects of CBD. Here we used two-electrode voltage clamp electrophysiology to compare the actions of CBD with those of the major central endocannabinoid, 2-arachidonoyl glycerol (2-AG) on human recombinant GABAAreceptors (synaptic α1-6βγ2 and extrasynaptic α4β2δ) expressed on Xenopus oocytes. CBD and 2-AG were positive allosteric modulators at α1-6βγ2 receptors, with low micromolar potencies. The maximal level of enhancement seen with either CBD or 2-AG were on α2-containing GABAAreceptor subtypes, with approximately a 4-fold enhancement of the GABA EC5evoked current, more than twice the potentiation seen with other α-subunit receptor combinations. Further we observed β-subunit selectivity, whereby modulatory activity was higher at β2/β3 over β1 subunits. The β1-subunit homologous mutant β2(V436T) substantially diminished the efficacy of both drugs to a third of that obtained with wild-type β2 subunit combinations, but without changing potency. The potency of CBD increased and efficacy preserved in binary α1/α2β2 receptors indicating that their effects do not involve the classic benzodiazepine site. Exploration of extrasynaptic α4β2δ receptors revealed that both compounds enhanced GABA EC5evoked currents at concentrations ranging from 0.01-1μM. Taken together these results reveal a mode of action of CBD on specifically configured GABAAreceptors that may be relevant to the anticonvulsant and anxiolytic effects of the compound.
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Bakas
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: P S
authors.initials: PS
authors.lastname: van Nieuwenhuijzen
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia; School of Psychology, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: S O
authors.initials: SO
authors.lastname: Devenish
authors.affiliation: School of Psychology, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: I S
authors.initials: IS
authors.lastname: McGregor
authors.affiliation: Discipline of Pharmacology, The University of Sydney, Sydney, NSW 2006, Australia; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: J C
authors.initials: JC
authors.lastname: Arnold
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: mary.collins@sydney.edu.au.
authors.forename: M
authors.initials: M
authors.lastname: Chebib
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000494:pharmacology*; D002185:Cannabidiol / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D063388:Endocannabinoids / Q000494:pharmacology*; D005989:Glycerides / Q000494:pharmacology*; D006801:Humans; D021122:Protein Subunits / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D014981:Xenopus
chemical_list: D000927:Anticonvulsants; D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D005989:Glycerides; D021122:Protein Subunits; D011963:Receptors, GABA-A; D002185:Cannabidiol; C094503:glyceryl 2-arachidonate
keywords: 2-Arachidonoyl Glycerol (PubChem CID: 5282280); 2-Arachidonoyl glycerol; Cannabidiol; Cannabidiol (PubChem CID: 644019); Cannabinoids; Endocannabinoids; GABA(A) receptors