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author:("stittelaar, G")
1.  Head-to head comparison of mGlu1 and mGlu5 receptor activation in chronic treatment of absence epilepsy in WAG/Rij rats 
Neuropharmacology  2014;85:91-103.
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
PMCID: PMC4356528  PMID: 24859611
Absence epilepsy; Spike–wave discharges; WAG/Rij rats; VU0360172; RO0711401; Tolerance; Chronic treatment; Group I mGlu receptors
2.  Potentiation of mGlu5 receptors with the novel enhancer, VU0360172, reduces spontaneous absence seizures in WAG/Rij rats 
Neuropharmacology  2012;66:330-338.
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.
PMCID: PMC3787880  PMID: 22705340
Absence epilepsy; WAG/Rij rats; mGlu5 receptor; VU0360172; MTEP
3.  Neurochemical and Behavioral Features in Genetic Absence Epilepsy and in Acutely Induced Absence Seizures 
ISRN Neurology  2013;2013:875834.
The absence epilepsy typical electroencephalographic pattern of sharp spikes and slow waves (SWDs) is considered to be due to an interaction of an initiation site in the cortex and a resonant circuit in the thalamus. The hyperpolarization-activated cyclic nucleotide-gated cationic Ih pacemaker channels (HCN) play an important role in the enhanced cortical excitability. The role of thalamic HCN in SWD occurrence is less clear. Absence epilepsy in the WAG/Rij strain is accompanied by deficiency of the activity of dopaminergic system, which weakens the formation of an emotional positive state, causes depression-like symptoms, and counteracts learning and memory processes. It also enhances GABAA receptor activity in the striatum, globus pallidus, and reticular thalamic nucleus, causing a rise of SWD activity in the cortico-thalamo-cortical networks. One of the reasons for the occurrence of absences is that several genes coding of GABAA receptors are mutated. The question arises: what the role of DA receptors is. Two mechanisms that cause an infringement of the function of DA receptors in this genetic absence epilepsy model are proposed.
PMCID: PMC3664506  PMID: 23738145
4.  The effects of acute responsive high frequency stimulation of the subiculum on the intra-hippocampal kainic acid seizure model in rats 
Brain and Behavior  2012;2(5):532-540.
The effects of acute responsive high frequency stimulation (HFS) to the subiculum on seizures and interictal spikes were investigated in a semi-acute kainic acid (KA) induced seizure model in rats. Wistar rats (n = 15) were implanted with an electrode-cannula complex in the CA3 area, stimulation and recording electrodes in the subiculum and another recording electrode at the contralateral motor cortex. Two weeks later rats were injected repeatedly with KA (0.05 μg/0.1 μL) for 3 days with an interval of 48 h. HFS (125 Hz, 100 μsec) was delivered to the subiculum at a predetermined intensity range (100–500 μA) in the HFS group (n = 7) when seizures were visually detected, while no stimulation was delivered in the sham control group (n = 8). Various severities of seizures were obtained (Stage I–V) and all rats of both groups reached Stage V (Racine's scale) on Day 1. The HFS group had less focal seizures and a longer inter-focal seizure interval on Day 1. Interictal spike rate was also lower in the HFS group and decreased with injection days. Significant day effects were found for the latency, number of focal seizures, and duration of focal seizures and generalized seizures while differences between groups were no longer present. Responsive HFS did not disrupt ongoing seizures. However, focal seizures and interictal spikes were suppressed by HFS. Such anticonvulsant effects of acute subicular stimulation indicate that the subiculum is involved in seizure generation. The reduction of seizure sensitivity over the injection day reflects an intrinsic anticonvulsant mechanism.
PMCID: PMC3489806  PMID: 23139899
High frequency stimulation; responsive; stimulation; subiculum; temporal lobe epilepsy

Results 1-4 (4)