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Contains fulltext : 54512.pdf (Publisher’s version ) (Closed access) In this study, the effects of vigabatrin on spike-and-wave discharges (SWDs) were measured in WAG/Rij rats, an animal model of absence epilepsy. Vigabatrin was used with the aim of enhancing GABAergic neurotransmission, and in this way to investigate the role of this process in the properties of SWDs. The study was carried out both in the rat, in vivo, and also using a computational model, in order to test different mechanisms that may account for the changes in SWDs after vigabatrin. The model parameters, representing GABA levels, were changed according to the known, and assumed, mechanism of action of the drug. The results show that the computational model can most adequately simulate the data obtained in vivo on the assumption that the enhancement of GABAergic neurotransmission due to application of vigabatrin is most pronounced at the level of the thalamic relay nuclei (TC cells). Furthermore, vigabatrin was shown to affect both the SWD starting and stopping mechanisms, as reflected by hazard rates. Based on these results, we suggest that GABAergic neurotransmission in TC cells is actively involved in the SWD termination. 8 p.

Contains fulltext : 27383.pdf (Publisher’s version ) (Open Access) Contains fulltext : 56954.pdf (Publisher’s version ) (Open Access) It was aimed to further evaluate the role of the GABAergic neurotransmission system in the mechanisms underlying absence epilepsy. More specifically, the aim of this thesis is to investigate whether GABAergic neurotransmission is either quantitatively or qualitatively (or both) involved in the mechanisms underlying SWDs and whether this involvement is specifically determined by GABAA or GABAB mediated neurotransmission. To summarise, manipulation of different types of GABA receptors was shown to differentially affect the SWD activity. Systemic administration of GABA agonistic drugs resulted in an enhancement of SWD activity, with the exception of diazepam and loreclezole (discussed in 8.1.3.). It has been predicted that (relatively) enhancing GABAB-related neurotransmission in TC cells should slow down the peak frequency of SWDs (Destexhe, 1999; Destexhe and Sejnowski, 2003), which was confirmed in this thesis (chapter 4). Also, it was shown that hazard rate analysis can be a useful tool for hypothesising about the SWD starting and stopping mechanisms. Moreover, it was shown that this type of analysis might reveal more information on these mechanisms than the standard analysis of averages (of incidence and duration). In general, stimulation of GABAA receptors was shown to increase the probability of the generation of SWDs and to decrease the probability of the cessation of SWDs. Stimulation of GABAB receptors was also shown to increase the probability of SWD generation. Moreover, GABAB receptor activation not only decreased the probability of the stopping of a SWD, but also changed the course of this probability as the SWD lasts. Possible biological mechanisms responsible for these effects were discussed, and some possible types of drugs for the treatment of absence epilepsy were proposed. RU Radboud Universiteit Nijmegen, 07 februari 2006 Promotor : Coenen, A.M.L. Co-promotor : Rijn, C.M. van 141 p.

Item does not contain fulltext In the present study, the effects of vigabatrin on type I and type II SWDs in the EEG of rats were studied. Vigabatrin is an irreversible GABA transaminase inhibitor which increases, long lasting, GABA concentrations, thus affecting both GABAA and GABAB conductances. Type I SWDs occur abundantly in WAG/Rij rats, whereas this type is virtually absent in ACI rats. In ACI rats however, type II SWDs do occur. The type I SWDs were studied in WAG/Rij rats after inter-peritoneal injection of 15-500 mg/kg of vigabatrin, 6 hours after injection. The type II SWDs were studied in ACI rats after inter-peritoneal injection of 500 mg/kg of vigabatrin, 6 hours after injection. The incidence of both type I and type II SWDs was significantly increased after vigabatrin as compared to saline. The duration of type II SWDs was also increased after vigabatrin as compared to saline treatment, whereas the duration of type I SWDs was not affected. The peak-frequency of both type I and type II SWDs was decreased after vigabatrin. Thus, vigabatrin alters not only the incidence but also the morphology of both type I and type II SWDs. These results might fit well with predictions of a theoretical model, in which both GABAA and GABAB conductances are modulated, as proposed by Destexhe (1999).

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Contains fulltext : 64255.pdf (Publisher’s version ) (Open Access)

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Contains fulltext : 63618.pdf (Publisher’s version ) (Open Access)

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Item does not contain fulltext Vigabatrin and diazepam both are GABAergic drugs. Vigabatrin enhances the concentration of endogenous GABA by inhibiting GABA-transaminase, while diazepam enhances the efficacy of the endogenous GABA present. As may be expected, the clinical effects of the two drugs overlap: e.g. both have anti-epileptic effects and both decrease the level of vigilance. The similarity of the effects on the EEG is however less clear. During slow-wave sleep, in drug-free rats, the EEG consists of high-voltage delta waves. Despite the induction of sleep, diazepam enhances the power of the high frequency beta band. This phenomenon is called pharmacological dissociation. In contrast, vigabatrin has been shown to slow down the EEG; the power in the delta and theta bands increases while that of the beta band decreases. However in those studies behavioural changes were not taken into consideration. The aim of the present study was to investigate, in the rat, the effect of vigabatrin on behaviour and on behaviour-related EEG.