Investigation of the endocannabinoids in absence epilepsy : therapeutic implications for comorbid anxiety

Abstract

Childhood Absence Epilepsy (CAE) is a paediatric epilepsy causing significant morbidity among patients of both sexes. It is classically associated with absence seizures, episodes of staring associated with loss of consciousness and associated with spike-wave discharges (SWDs) on electroencephalogram (EEG). Absence seizures, however, are only partially the cause of the poor quality of life in these patients. Studies have shown that around 60% of patients with CAE report neuropsychiatric comorbidities which accompany this disease, most importantly, attention deficit disorders, anxiety and depression. Past research has shown a key involvement of the endocannabinoid system (ECS) and its interplay with the monoamine systems in the development of CAE but their involvement in psychiatric comorbidities has not yet been investigated. This study focused on anxiety-like behavioural changes in genetic absence epilepsy rats from Strasburg (GAERS), an animal model of CAE, after administration of the potent non-selective cannabinoid 1 and 2 receptor (CB1/2R) agonist, WIN55,212-2, and its vehicle. This drug was also administered to a group of non-epileptic control rats (NEC), and anxiety-like and motor behavioural changes were evaluated in two commonly used behavioural tests for anxiety, i.e., hole board (HB) and elevated plus maze (EPM). Moreover, we investigated the monoamine systems in absence epilepsy and their interaction with the ECS by measuring the brain concentrations of serotonin, noradrenalin and dopamine. The present study revealed a level of anxiety which is higher in NEC rats when contrasted with the epileptic GAERS rats treated with WIN55,212-2’s vehicle. Moreover, WIN55,212- 2 produced strain-dependent changes in the behaviour of the animals, namely an anxiolytic effect in NEC and a sedative effect in GAERS. These changes were accompanied by neurochemical changes in specific brain areas, for instance, lower serotonin levels were detected in the GAERS cortex, dorsal hippocampus and the substantia nigra compared to NEC. Although many questions remain unanswered, our findings collectively add to the evidence of a pathological change in the endocannabinoid system in patients with absence epilepsy. Further mechanistic studies are required to explain the current evidence which may ultimately benefit patients’ treatment.