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Modulation of the endocannabinoid system in Genetic Absence Epilepsy Rats from Strasbourg: New avenues for treatment of absence seizures and behavioural comorbidities.



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Current treatments for Absence Epilepsy (AE) are insufficient and do not adequately manage seizures and comorbidities in most patients. With the recent legalization of cannabis in Canada, interest in its use for the treatment of epilepsy has increased. However, no studies have assessed cannabis in AE, and only limited preclinical evidence is available. Using Genetic Absence Epilepsy Rats from Strasbourg (GAERS), this thesis examines how cannabis-based medicines may be used to treat seizures and behavioural comorbidities relevant to AE. In Chapter 2, touchscreen chambers were used to identify visual learning and flexibility impairments in GAERS. These findings provide evidence of cognitive impairment, suggesting GAERS may be used to model this comorbidity. In Chapter 3, we tested the effects of plant-derived phytocannabinoids on seizures in GAERS. Injected Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent in cannabis, increased the number of seizure events as measured by increased spike-and slow wave discharges (SWDs) recorded through electroencephalogram (EEG). In contrast, cannabidiol (CBD) produced a moderate decrease in SWDs. As cannabis is usually smoked, we used a novel smoke exposure protocol to subject animals to high-THC and high-CBD cannabis smoke. Consistent with the injection data, high-THC smoke increased SWDs whereas high-CBD smoke had no effect. These findings are the first to demonstrate a seizure modulating effect of THC and CBD in a rat model of AE. Chapter 4 characterized the endocannabinoid system (ECS) in GAERS and investigated whether type 1 cannabinoid receptor (CB1R) positive allosteric modulators (PAMs) may be effective in reducing SWDs. Sex-specific and regional alterations in the ECS were identified which may contribute to seizure propagation and behavioural comorbidities in GAERS. These experiments also demonstrated that the CB1R PAMs GAT211 and GAT229 reduce SWDs in GAERS without producing adverse behavioural effects observed following THC exposure. In Chapter 5, GAT211 was tested to determine whether it could also reverse behavioural impairments observed in GAERS. This experiment used a battery assessing anxiety-like behaviour and social impairment as these deficits have previously been shown to respond to antiepileptic drug treatment. These data provided some evidence to suggest a potential therapeutic effect of GAT211, but future experiments will be required to confirm these results. Overall, these data identify additional comorbidities, and demonstrate seizure modulating effects of several cannabinoids. The seizure reducing effects of CBD, GAT211, and GAT229 highlight the potential use of cannabinoids in GAERS as a promising area for continued preclinical research in AE.



Cannabis, epilepsy, seizures, cannabidiol,



Doctor of Philosophy (Ph.D.)






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