Altered SWD stopping mechanism in WAG/Rij rats subchronically treated with the cannabinoid agonist R(+)WIN55,212-2

Abstract

A single injection of the cannabinoid agonist R(+)WIN55,212-2 (WIN) is known to cause an increase of the mean duration of spontaneously occurring spike-and-wave discharges (SWDs) in rats of the WAG/Rij strain, a genetic model for absence epilepsy. The aim of the present study was to establish whether repeated activation of CB 1 receptors with WIN leads to tolerance in its effect on SWD parameters, spectral density, and behavior over time. Adult male WAG/Rij rats (n = 16) were treated with WIN (6 mg/kg) or vehicle (olive oil). Injections (s.c.) took place 3 times per week during 2 weeks. Electroencephalogram (EEG) recordings, each lasting 24 h, were made 3 times: immediately before the first injection (baseline), immediately after the first injection (acute treatment), and after 2 weeks of treatment (subchronic treatment). The recordings were analyzed regarding incidence, durations of SWDs, and hazard rates of the durations of SWDs, the latter to describe SWD stopping probabilities. Putative changes in the spectral content of the EEG before and after WIN during active and passive behaviors were additionally investigated. Spike-and-wave discharge incidence was not affected by the acute and subchronic treatments. The mean duration of the SWDs was significantly longer than controls in the acute WIN-treated animals [11.9-s standard error of the mean (SEM): 0.64 compared with 8.4-s SEM: 0.25] as well as in subchronically treated animals (11.5-s SEM: 1.00 compared with 8.4-s SEM: 0.25). Hazard rates were significantly lower for WIN-treated animals at SWD durations in the 5.04-20.16-s range on both occasions. No effects of WIN on the frequency spectrum of the ongoing EEG were found, neither acutely nor after repeated administration. Evidence for tolerance was not found. The results on the mean duration and hazard rates suggest that stimulating the endocannabinoid system affects the SWD stopping mechanism, resulting in more long SWDs. We speculate that this effect is likely to be a direct result of CB 1 receptor agonism and a subsequent decrease in the availability of gamma-aminobutyric acid (GABA) in the reticular thalamic nucleus, which further weakens, in WAG/Rij rats already disturbed, the stopping mechanism of the SWDs.

Cannabinoid 1/2 Receptor Activation Induces Strain-Dependent Behavioral and Neurochemical Changes in Genetic Absence Epilepsy Rats From Strasbourg and Non-epileptic Control Rats

“…To achieve this goal, we need to further our understanding of the bidirectional link between anxiety and epilepsy ( Kanner, 2013 ) and the underlying mechanisms, genetic predisposition, neuronal excitability alterations, and anatomical pathways ( Hingray et al, 2019 ) that these psychiatric and neurological disorders may share. For instance, ASs and anxiety are linked to different alterations in neurotransmitters, such as monoamines ( Marescaux et al, 1992 ; Svob Strac et al, 2016 ; Venzi et al, 2016 ; Crunelli et al, 2020 ) and endocannabinoids (eCBs) ( van Rijn et al, 2010 ; Perescis et al, 2020 ; Roebuck et al, 2020 , 2021 ), which are likely to interact with each other ( Colangeli et al, 2021 ). However, these interactions have not been studied yet in comorbid anxiety of animal models of CAE.…”

Dissociable changes in spike and wave discharges following exposure to injected cannabinoids and smoked cannabis in Genetic Absence Epilepsy Rats from Strasbourg

“…The THC‐induced increase in SWDs supports previous studies conducted in the WAG/Rij model of AE. Using the full CB1R agonist WIN‐55212‐2, researchers reported moderate anti‐epileptic effects but also observed concerning rebounds and increases in seizure events (Citraro, Russo, Ngomba, et al., 2013; Citraro, Russo, Scicchitano, et al., 2013; Perescis et al., 2020; van Rijn et al., 2010; Smolyakova et al., 2020). Although these studies were conducted in a different model using a more potent synthetic agonist, they appear consistent with our findings in GAERS.…”

“…It is important to note that THC and CBD pharmacology is complex and both molecules bind receptors beyond the ECS (Perucca, 2017). In the WAG/Rij rat model of AE, disruption of the ECS has also been observed and administration of synthetic CB1R agonists has shown both pro‐ and anti‐epileptic effects (Citraro, Russo, Ngomba, et al., 2013; Citraro, Russo, Scicchitano, et al., 2013; Perescis et al., 2020; van Rijn et al., 2010). Whether similar effects are observed in GAERS needs to be tested.…”

From Physiology to Pathology of Cortico-Thalamo-Cortical Oscillations: Astroglia as a Target for Further Research

“…In situ hybridization and Western blot analysis showed reduced levels of CB1 receptor mRNA and protein in the NRT and of the CB1 receptor in the thalamus of WAG/Rij rats at the protein level, thereby suggesting an impaired depolarization-induced CB1-mediated suppression of inhibition ( 197 ). Indeed, acute systemic injection of the synthetic CB1 receptor agonist WIN55,212-2 resulted in a transient reduction in SWDs frequency, however surprisingly followed by an increase in SWD duration in subchronic treatment ( 144 , 197 – 199 ). Since the beneficial effects of the endocannabinoid ANA, previously described, last longer than the transient reduction in SWD frequency induced by the synthetic CB1 agonist and since ANA does indeed shorten SWDs, its mechanism of action is likely not only dependent on CB1 activation but a more complex molecular process ( 144 ).…”