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Contains fulltext : 56060.pdf (publisher's version ) (Closed access), The effects of vigabatrin, which increases GABA concentrations by inhibiting GABA transaminase, on spike and wave discharges (SWDs) in the electroencephalogram of WAG/Rij rats were studied. Vigabatrin increased the incidence and duration of the SWDs, suggesting a quantitative GABA(A)ergic involvement in the mechanism(s) underlying the starting and stopping of an ongoing SWD. Also, vigabatrin decreased the SWD peak frequency, suggesting an important role of GABA(B) in the mechanism(s) underlying the peak frequency of the SWDs. Vigabatrin gradually changed the course of the hazard rates of the SWD durations, suggesting a quatitative GABAergic role in the mechanism(s) underlying the stopping of an ongoing SWD.

RU Radboud Universiteit Nijmegen, 07 februari 2006, Promotor : Coenen, A.M.L. Co-promotor : Rijn, C.M. van, Contains fulltext : 56954.pdf (publisher's version ) (Closed 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.

Contains fulltext : 54678.pdf (publisher's version ) (Closed access), In this paper, we investigate the dynamical scenarios of transitions between normal and paroxysmal state in epilepsy. We assume that some epileptic neural network are bistable i.e., they feature two operational states, ictal and interictal that co-exist. The transitions between these two states may occur according to a Poisson process, a random walk process or as a result of deterministic time-dependent mechanisms. We analyze data from animal models of absence epilepsy, human epilepsies and in vitro models. The distributions of durations of ictal and interictal epochs are fitted with a gamma distribution. On the basis of qualitative features of the fits, we identify the dynamical processes that may have generated the underlying data. The analysis showed that the following hold. 1) The dynamics of ictal epochs differ from those of interictal states. 2) Seizure initiation can be accounted for by a random walk process while seizure termination is often mediated by deterministic mechanisms. 3) In certain cases, the transitions between ictal and interictal states can be modeled by a Poisson process operating in a bistable network. These results imply that exact prediction of seizure occurrence is not possible but termination of an ictal state by appropriate counter stimulation might be feasible.

Contains fulltext : 54832.pdf (publisher's version ) (Closed access), We show that the hazard function provides useful information about the starting and the stopping mechanisms of absence epileptic seizures. The hazard function quantifies changes in the probability that an event (respectively, the starting and the stopping of a seizure) occurs in some small time interval given that it has not occurred yet. It informs us about changes in the concentration of endogenous substances that modulate the neuronal signalling properties of (parts of) the brain. In a pharmacological experiment, we used the hazard function to study the effect of a GABA-transaminase inhibitor (vigabatrin) on the starting and the stopping mechanisms of absence epileptic seizures in a genetic rat model of absence epilepsy (the WAG/Rij rat). This experiment showed that a high GABA level changed the stopping mechanism of the absence epileptic seizures, creating much better conditions for very long seizures to develop. With respect to the starting mechanism, it was found that both with a high and a low GABA level, there was evidence for a recovery mechanism that decreases the probability that a new seizure starts. Initially, this probability is larger with a high GABA level, but gradually it converges to the same constant baseline probability as in the condition with a low GABA level.

Contains fulltext : 54753.pdf (publisher's version ) (Closed access), The relationship between hippocampal electroencephalogram (EEG) theta activity and locomotor speed in both spontaneous and forced walking conditions was studied in rats after vigabatrin injection (500 mg/kg i.p.). Vigabatrin increased the percentage of time that rats spent being immobile. During spontaneous walking in the open field, the speed of locomotion was increased by vigabatrin, while theta peak frequency was decreased. Vigabatrin also reduced the theta peak frequency during forced (speed controlled) walking. There was only a weak positive correlation (r = 0.22) between theta peak frequency and locomotor speed for the saline condition. Furthermore, vigabatrin abolishes the weak relationship between speed of locomotion and theta peak frequency. Vigabatrin and saline did not differ in the slope of the regression line, but showed different offset points at the theta peak frequency axis. Thus, other factors than speed of locomotion seem to be involved in determination of the theta peak frequency.

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Contains fulltext : 64262.pdf (publisher's version ) (Closed access), Effects of the novel anti-epileptic drug levetiracetam (50 and 100 mg/kg) on spike and wave discharges (SWDs) of WAG/Rij rats were studied. Levetiracetam decreased the incidence, average duration, total duration and peak frequency of the SWDs. There was no difference between the two doses. These results agree with results obtained in Genetic Absence Epilepsy Rat from Strasbourg (GAERS). Furthermore, the decrease of the SWD peak frequency might support the suggestions that levetiracetam might have a GABAergic mechanism of action.

Proceedings of the 13th Biennial Meeting of the International Pharmaco-EEG Group (IPEG), Antwerp, Belgium, 10-12 September 2004, Item does not contain fulltext

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).

Contains fulltext : 64514.pdf (publisher's version ) (Closed access), To test whether polytherapy with two gamma-aminobutyric acid (GABA) -ergic drugs might be clinically relevant for epilepsy treatment, effects on spike and wave discharges, the fraction of time spent being behaviourally active, and the background electroencephalogram (EEG) during behavioural activity of vigabatrin (15 - 500 mg/kg i.p.) and diazepam (1.25 - 10 mg/kg i.p.) were compared with their combination (dose ratio 1:25) in rats. Isobolic analyses were performed to describe the interactions. Unfortunately, no conclusions can be drawn concerning the interaction of both drugs on the spike and wave discharge activity because the effect of diazepam was shown to be dominant. Only vigabatrin decreased the behavioural activity, whereas there was a trend towards a decrease after diazepam. All treatments dose dependently increased the power in the beta frequency band. Unfortunately, the dose ratio was not optimal to describe the interaction. The theta peak frequency was dose dependently decreased after all treatments. There was a synergistic interaction between the two drugs on this variable. These data support both the idea that an increase in power in the beta frequency band can serve as a biomarker for GABAergic inhibition and the suggestion that clinically effective anxiolytics decrease the theta peak frequency. Furthermore, we show that on different variables, there might be different optimal dosage combinations, which might complicate the clinical application of polytherapy.

Contains fulltext : 63317.pdf (publisher's version ) (Closed access), Effects of vigibatrin (saline, 125, 250, or 500 mg/kg i.p.) on spontaneous locomotor activity in Wistar rats were investigated. There was a dose dependent decrease in amount of locomotion for doses up to 250 mg/kg. This decrease was measurable 2-4 hours after injection and still became more pronounced in the following hours. The mean velocity during the movements 2-6 hours after injection remained intact and was higher in the 500 mg/kg group. In this high dose group an abnormal posture with a hunched back and pilo-erection was observed. The decrease of the amount of motor activity with the preservation of the mean velocity in this non-stimulating procedure, suggests that the level in which the experimental procedure imposes motor activity might be an important factor when measuring effects of vigabatrin. Postscript: Immediate post injection effects were observed, equivalent to those seen in the writhing test, a pain test using hyperosmolar saline injections. These observations stress the importance of controlling the osmolarity of the injection fluids.

Item does not contain fulltext, The antiepileptic drug vigabatrin increases GABA concentrations by inhibiting GABA transaminase. The effects of vigabatrin on type 11 spike wave discharges (SWDs) in the electroencephalogram of ACI rats were studied in order to learn more about the effects of altering GABA concentration on SWDs. The incidence of type II SWDs increased after vigabatrin (60/h) as compared to saline treatment (3.7/h). This effect appeared with a halftime of 100 min. The duration of type II SWDs increased after vigabatrin (1.52 s) as compared to saline treatment (1.04 s), but the peak-frequency of the type 11 SWDs decreased after vigabatrin (5.6 Hz) as compared to saline treatment (7.5 Hz). Thus, vigabatrin alters the type II SWD morphology. These results are in agreement with predictions of Destexhe's theoretical model, modulating both GABA(A) and GABA(B) conductances.

Item does not contain fulltext, Schizophrenia patients subjected to the A-X Continuous Performance Test (A-X CPT) show cognitive deficits that are thought to reflect impaired representation and maintenance of context information. An issue deserving attention is to what extent the acute amphetamine model of schizophrenia also models these cognitive deficits. The present experiment examined the effect of acute d-amphetamine (AMP) on the performance of rats in an animal analogue of the A-X CPT. Subjects first learned to solve an A->X+, B->X-, A->Y-discrimination task, with A and B representing visual features; X and Y designating auditory target stimuli; -> signifying a serial presentation; and + and - referring to food reinforcement and non-reinforcement, respectively. Frequency of food-magazine visits was the dependent measure. After mastering the discrimination, rats received test trials under either saline or 0.5 mg/kg AMP (s.c.). At test, the interval between feature and target presentation was varied; reinforcement contingencies were maintained. AMP significantly impaired performance on the A->X+/B->X- discrimination by increasing the response level on B->X- trials. AMP did not significantly affect performance on the A->X+/A->Y- discrimination. However, AMP also increased magazine responding in the absence of the presentation of features and targets. A parsimonious conclusion based on these preliminary results is that acute AMP does not affect processing of context information provided by the visual features in this procedure. It rather has a more non-specific response-enhancing effect, especially with respect to stimuli associated with the delivery of food.