WAG/Rij 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

Rijn, Clementina M. van; Gaetani, Silvana; Santolini, Ines; Badura, Aleksandra; Gabova, Aleksandra; Fu, Jin; Watanabe, Masashiko; Cuomo, V.; Luijtelaar, Gilles van; Nicoletti, Ferdinando; Ngomba, Richard Teke

doi:10.1111/j.1528-1167.2009.02510.x

Cited by 57 publications

(47 citation statements)

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“…Interestingly, pharmacological activation of CB1 receptors reduces absence seizures in WAG/Rij rats (van Rijn et al, 2010). It is worth noting that systemic injection of drugs that enhance synaptic GABA levels, such as tiagabine and vigabatrin, enhance SWDs in GAERS and WAG/Rij rats (Coenen et al, 1995; Depaulis and van Luijtelaar, 2006; Bouwman et al, 2007), and similar effects are seen following bilateral injections of γ-vinyl GABA or the GABA A receptor agonist, muscimol, into the medial part of the ventral lateral thalamus containing thalamic relay nuclei (Liu et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

“…ACI rats have no or only very few SWDs and the lowest number of SWDs of all inbred strains investigated as was assessed in a 48 h EEG evaluation study (Inoue et al, 1990) and in all cases they have much less SWDs than WAG/Rij rats of the same age (Schridde and van Luijtelaar, 2004). Therefore, ACI rats are commonly used as controls in experiments with WAG/Rij rats (Lasoń et al, 1992; Ngomba et al, 2008; van de Bovenkamp-Janssen et al, 2006; van Rijn et al, 2010). We used rats of both strains at 2 and 8 months of age.…”

Section: Methodsmentioning

confidence: 99%

“…Spontaneous motor activity in symptomatic WAG/Rij rats was recorded with an analogic passive infrared detector (PIR) (Luna PR, Rokonet Electronics LTD, Rishon Le Tzion, Israel) (van Rijn et al, 2010) during the EEG recording session. The analogue signal was digitalized simultaneously with the EEG signal.…”

Section: Methodsmentioning

confidence: 99%

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Potentiation of mGlu5 receptors with the novel enhancer, VU0360172, reduces spontaneous absence seizures in WAG/Rij rats

et al. 2013

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Absence epilepsy is generated by the cortico-thalamo-cortical network, which undergoes a finely tuned regulation by metabotropic glutamate (mGlu) receptors. We have shown previously that potentiation of mGlu1 receptors reduces spontaneous occurring spike and wave discharges (SWDs) in the WAG/Rij rat model of absence epilepsy, whereas activation of mGlu2/3 and mGlu4 receptors produces the opposite effect. Here, we have extended the study to mGlu5 receptors, which are known to be highly expressed within the cortico-thalamo-cortical network. We used presymptomatic and symptomatic WAG/Rij rats and aged-matched ACI rats. WAG/Rij rats showed a reduction in the mGlu5 receptor protein levels and in the mGlu5-receptor mediated stimulation of polyphosphoinositide hydrolysis in the ventrobasal thalamus, whereas the expression of mGlu5 receptors was increased in the somatosensory cortex. Interestingly, these changes preceded the onset of the epileptic phenotype, being already visible in pre-symptomatic WAG/Rij rats. SWDs in symptomatic WAG/Rij rats were not influenced by pharmacological blockade of mGlu5 receptors with MTEP (10 or 30 mg/kg, i.p.), but were significantly decreased by mGlu5 receptor potentiation with the novel enhancer, VU0360172 (3 or 10 mg/kg, s.c.), without affecting motor behaviour. The effect of VU0360172 was prevented by co-treatment with MTEP. These findings suggest that changes in mGlu5 receptors might lie at the core of the absence-seizure prone phenotype of WAG/Rij rats, and that mGlu5 receptor enhancers are potential candidates to the treatment of absence epilepsy.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Potentiation of mGlu5 receptors with the novel enhancer, VU0360172, reduces spontaneous absence seizures in WAG/Rij rats

et al. 2013

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“…In contrast, focal administration of the CB1R antagonist/inverse agonist SR141716 (rimonabant) had pro-convulsant effects and blocked the anti-absence effects of anandamide in this model (Citraro et al, 2013b). Accordingly, cannabinoid CB 1 receptors (CB 1 Rs) are known to be downregulated in the NRT of WAG/Rij rats suggesting a generally lowered sensitivity to released eCBs (van Rijn et al, 2010).…”

Section: Endogenous Cannabinoidsmentioning

confidence: 96%

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

Russo

Citraro

Constanti³

et al. 2016

Neuroscience & Biobehavioral Reviews

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128

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Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development.Neuroscience and Biobehavioral Reviews http://dx.doi.org/10. 1016/j.neubiorev.2016.09.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe WAG/Rij rat model has recently gathered attention as a suitable animal model of absence epileptogenesis. This latter term has a broad definition encompassing any possible cause that determines the development of spontaneous seizures; however, most of, if not all, preclinical knowledge on epileptogenesis is confined to the study of post-brain insult models such as traumatic brain injury or post-status epilepticus models. WAG/Rij rats, but also synapsin 2 knockout, Kv7 current-deficient mice represent the first examples of genetic models where an efficacious antiepileptogenic treatment (ethosuximide) was started before seizure onset. In this review, we have critically reconsidered all articles published regarding WAG/Rij rats, from the perspective that the period before SWD onset is considered as the latent period. In our new theory on seizure development, it is proposed that genes might be considered as the initial "insult" responsible for all plastic changes underpinning the development of spontaneous seizures. According to this idea, in WAG/Rij rats, genetic predisposition would lead to the development of abnormal bilateral cortical epileptic foci, which would then nongenetically stimulate the rest of the brain to rearrange networks in order to phenotypically develop seizures similarly to what happens during electrical kindling.

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“…Spontaneous motor activity was recorded as previously reported (van Rijn et al, 2010); an analogic passive infrared detector (PIR) (Luna PR, Rokonet Electronics LTD, Rishon Le Tzion, Israel) was fixed to a semi-open lid on top of the each rat’s EEG recording cage. The analogue signal was digitalized simultaneously with the EEG signal.…”

Section: Methodsmentioning

confidence: 99%

Head-to head comparison of mGlu1 and mGlu5 receptor activation in chronic treatment of absence epilepsy in WAG/Rij rats

et al. 2014

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Acute treatment with positive allosteric modulators (PAMs) of mGlu1 and mGlu5 metabotropic glutamate receptors (RO0711401 and VU0360172, respectively) reduces the incidence of spike-and wave discharges in the WAG/Rij rat model of absence epilepsy. However, from the therapeutic standpoint, it was important to establish whether tolerance developed to the action of these drugs. We administered either VU0360172 (3 mg/kg, s.c.) or RO0711401 (10 mg/kg, s.c.) to WAG/Rij rats twice daily for ten days. VU0360172 maintained its activity during the treatment, whereas rats developed tolerance to RO0711401 since the 3rd day of treatment and were still refractory to the drug two days after treatment withdrawal. In response to VU0360172, expression of mGlu5 receptors increased in the thalamus of WAG/Rij rats after 1 day of treatment, and remained elevated afterwards. VU0360172 also enhanced mGlu5 receptor expression in the cortex after 8 days of treatment without changing the expression of mGlu1a receptors. Treatment with RO0711401 enhanced the expression of both mGlu1a and mGlu5 receptors in the thalamus and cortex of WAG/Rij rats after 3–8 days of treatment. These data were different from those obtained in non-epileptic rats, in which repeated injections of RO0711401 and VU0360172 down-regulated the expression of mGlu1a and mGlu5 receptors. Levels of VU0360172 in the thalamus and cortex remained unaltered during the treatment, whereas levels of RO0711401 were reduced in the cortex at day 8 of treatment. These findings suggest that mGlu5 receptor PAMs are potential candidates for the treatment of absence epilepsy in humans

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WAG/Rij 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

Cited by 57 publications

References 46 publications

Potentiation of mGlu5 receptors with the novel enhancer, VU0360172, reduces spontaneous absence seizures in WAG/Rij rats

Potentiation of mGlu5 receptors with the novel enhancer, VU0360172, reduces spontaneous absence seizures in WAG/Rij rats

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

Head-to head comparison of mGlu1 and mGlu5 receptor activation in chronic treatment of absence epilepsy in WAG/Rij rats

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