The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA receptors

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 GABA(A) receptors, 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 GABA(A) receptors (synaptic alpha 1-6 beta gamma 2 and extrasynaptic alpha 4 beta 2 delta) expressed on Xenopus oocytes. CBD and 2-AG were positive allosteric modulators at alpha 1-6 beta gamma 2) receptors, with low micromolar potencies. The maximal level of enhancement seen with either CBD or 2-AG were on alpha 2-containing GABA(A) receptor subtypes, with approximately a 4-fold enhancement of the GABA EC5 evoked current, more than twice the potentiation seen with other alpha-subunit receptor combinations. Further we observed beta-subunit selectivity, whereby modulatory activity was higher at beta 2/beta 3 over beta 1 subunits. The beta 1-subunit homologous mutant beta 2(V436T) substantially diminished the efficacy of both drugs to a third of that obtained with wild-type beta 2 subunit combinations, but without changing potency. The potency of CBD increased and efficacy preserved in binary alpha 1/alpha 2 beta 2 receptors indicating that their effects do not involve the classic benzodiazepine site. Exploration of extrasynaptic alpha 4 beta 2 delta receptors revealed that both compounds enhanced GABA EC5 evoked currents at concentrations ranging from 0.01-1 mu M. Taken together these results reveal a mode of action of CBD on specifically configured GABA(A) receptors that may be relevant to the anticonvulsant and anxiolytic effects of the compound. (C) 2017 Elsevier Ltd. All rights reserved.