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Title: Modulation of inhibitory receptors by cannabidiol and cannabidivarin
Author: Branco De Assis Manuel, Joana
ISNI:       0000 0004 8500 080X
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Type A γ-aminobutyric acid (GABAA) and glycine receptors are ligand-gated ion channels that mediate fast inhibitory neurotransmission in the nervous system. As such, they represent important targets in the management of epilepsy, a hyperexcitability disorder where pharmacological manipulation of inhibitory synaptic transmission can lead to viable therapeutic treatments. Research into new drugs for intractable epilepsy is ongoing, with cannabinoids emerging as a new class of anticonvulsants. Indeed, the non-psychotropic phytocannabinoids cannabidiol (CBD) and cannabidivarin (CBDV) have shown promising results in preclinical models of epilepsy. Moreover, clinical trials leading to the recent approval of a CBD-containing medicine by the Food and Drug Administration in the United States have further highlighted the therapeutic potential of CBD in paediatric epilepsy disorders characterized by drug-resistant seizures. However, the precise mechanisms by which these non-psychoactive phytocannabinoids exert their anticonvulsant effects are unknown though several plausible targets have previously been described. A number of studies have shown a direct modulation of GABAA and glycine receptors by cannabinoids, though the action of CBD and CBDV on these receptors has not been systematically examined. Thus, the objective of this research was to assess the effect of CBD and CBDV on Cl- currents mediated by GABA or glycine (IGABA or Igly). Whole-cell patch-clamp recordings from HEK293 cells transiently expressing different GABAA receptor subtypes, including the most common isoforms α1β2γ2 and α2β2γ2, revealed a transient potentiation of IGABA in the presence of CBD or CBDV. This effect was not dependent on the presence of the GABAA receptor γ2 subunit. Moreover, site-directed mutagenesis indicated that IGABA potentiation by CBD and CBDV was independent of the benzodiazepine binding site. This was in line with data demonstrating an additive modulation of IGABA by phytocannabinoids applied in combination with the benzodiazepine diazepam. In addition, both CBD and CBDV potentiated δ-containing GABAA receptors, which are known to mediate tonic inhibition. In contrast to the transient potentiation of IGABA, the phytocannabinoids induced a progressive and sustained enhancement of Igly mediated by homomeric glycine receptors containing the α1, α2 or α3 subunits. Finally, the effect of CBD and CBDV on IGABA was examined in acute hippocampal slices from young adult mice. In contrast with the data obtained in HEK293 cells, superfusion of CBD had no effect on GABAergic currents elicited in CA1 pyramidal neurones, whilst CBDV had a slight inhibitory effect. Overall, the findings presented in this thesis uncover a direct enhancement of the function of inhibitory receptors by CBD and CBDV, thus offering new opportunities for therapeutic intervention in the nervous system and shedding light on the mechanism of action of non-psychoactive phytocannabinoids.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available