A GABA-A receptor response to CBD following status epilepticus in the medial entorhinal cortex of the rat

Cannabidiol is a non-psychoactive phytocannabinoid that has been implicated as a potential therapeutic in numerous neurological diseases. Perhaps the most widespread therapeutic use of CBD has been in the form of Epidiolex, which is used to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome and tuberous sclerosis. Whilst the effectiveness of CBD in seizure reduction is clear, its mechanism of action is complex, and reflects the wide range of pharmacodynamic targets that includes receptors, ion channels and enzymes. This study investigated the effects of action of cannabidiol (CBD) on GABAergic transmission in layer II of the medial entorhinal cortex in animals that had previously undergone a period of status epilepticus (SE). Spontaneous post-synaptic currents were recorded from medial entorhinal cortex layer II pyramidal cells in animals 1-7 after SE and in age matched controls as well as in tissue resected from children with temporal lobe epilepsy (TLE). CBD enhanced GABAAR-mediated inhibition by increasing decay times and inhibitory charge transfer across the postsynaptic membrane in status epilepticus (SE) but did not alter GABAergic transmission in age-matched control rats. The SE-induced effects of CBD were blocked by ligands acting as inverse agonists at the benzodiazepine site of the GABAAR receptor and the effects of CBD were additive to low-doses of benzodiazepine and barbiturate agonists, consistent with allosteric actions on the GABAAR. Similar effects were observed in both SE rat and human layer II neurons. Overall, these data suggest CBD may act as a positive allosteric modulator (PAM) at postsynaptic GABAARs and this action appears to develop following SE. Key pointsO_LICBD increases inhibition only post status epilepticus. C_LIO_LIThis effect is blocked by benzodiazepine site inverse agonists C_LIO_LICBD is additive to low-dose zolpidem, suggesting an allosteric effect on the GABAAR C_LIO_LICBD was similarly effective in ex vivo human epileptic tissue C_LIO_LIThese results suggest CBD is a positive allosteric modulator at the GABAAR C_LI