WAGRij rats show a reduced expression of CB1 receptors in thalamic nuclei and respond to the CB1 receptor agonist, R(+)WIN55,212-2, with a reduced incidence of spike-wave discharges

Abstract

Purpose: Genetically epileptic WAGRij rats develop spontaneous absence-like seizures after 3 months of age. We used WAGRij rats to examine whether absence seizures are associated with changes in the expression of type-1 cannabinoid (CB1) receptors. Methods: Receptor expression was examined by in situ hybridization and western blot analysis in various brain regions of "presymptomatic" 2-month old and "symptomatic" 8-month-old WAGRij rats relative to age-matched nonepileptic control rats. Furthermore, we examined whether pharmacologic activation of CB1 receptor affects absence seizures. We recorded spontaneous spike-wave discharges (SWDs) in 8-month old WAGRij rats systemically injected with the potent CB1 receptor agonist, R(+)WIN55,212-2 (3-12 mgkg, s.c.), given alone or combined with the CB1 receptor antagonistinverse agonist, AM251 (12 mgkg, s.c.). Results: Data showed a reduction of CB1 receptor mRNA and protein levels in the reticular thalamic nucleus, and a reduction in CB 1 receptor protein levels in ventral basal thalamic nuclei of 8-month-old WAGRij rats, as compared with age-matched ACI control rats. In vivo, R(+)WIN55,212-2 caused a dose-dependent reduction in the frequency of SWDs in the first 3 h after the injection. This was followed by a late increase in the mean SWD duration, which suggests a biphasic modulation of SWDs by CB 1 receptor agonists. Both effects were reversed or attenuated when R(+)WIN55,212-2 was combined with AM251. Discussion: These data indicate that the development of absence seizures is associated with plastic modifications of CB1 receptors within the thalamic-cortical-thalamic network, and raise the interesting possibility that CB1 receptors are targeted by novel antiabsence drugs. © 2010 International League Against Epilepsy.