J.M.H. Vossen

Spike-wave discharges and sleep-wake states in rats with absence epilepsy

The occurrence of spike-wave discharges was studied in relation to the daily fluctuations of vigilance level in rats. Eight rats of the WAG/Rij strain, an animal model for idiopathic generalized epilepsy of the absence type, which were equipped with cortical EEG and nuchal EMG electrodes, served as subjects. It was found that spike-wave discharges predominantly occur during light slow wave sleep and passive wakefulness. REM sleep, active wakefulness, and deep slow wave sleep are less susceptible to the occurrence of spike-wave discharges. Finally, spike-wave discharges tend to prevail in transitional states. A crucial role for the degree of stability of the level of vigilance in the genesis of absence seizures is suggested.

Effects of GABA-ergic agents on spontaneous non-convulsive epilepsy, EEG and behaviour, in the WAG/Rij inbred strain of rats

The effects of GABAergic agents on non-convulsive epilepsy were studied by intracerebroventricular injections of muscimol and bicuculline in WAG/Rij rats. The WAG/Rij rat strain is recognized as an animal model for human absence epilepsy. EEG registrations and behavioural observations showed that muscimol dose-dependently increased the non-convulsive absence epilepsy. Besides this, it induced EEG spikes and body twitches. Bicuculline induced spikes and body twitches as well but decreased the non-convulsive epilepsy. All effects of muscimol can be blocked by bicuculline and vice versa, which suggests that the observed effects are genuine GABAA effects. These results implicate that non-convulsive epilepsy can be caused by a GABAergic hyperfunction.

Involvement of NMDA receptors in non-convulsive epilepsy in WAG/Rij rats.

The involvement of the NMDA receptor in spontaneous non-convulsive epilepsy was studied by intracerebroventricular injections of APH and NMDA in WAG/Rij rats. The WAG/Rij rat strain is recognized as an animal model for human absence epilepsy. EEG registrations showed that APH (5 nmol/5 microliters; 25 nmol/5 microliters; 50 nmol/5 microliters) causes a dose-dependent decrease in the number and mean duration of the spike-wave discharges, while NMDA (50 pmol/5 microliters; 500 pmol/5 microliters; 5 nmol/5 microliters) induces a dose-dependent increase in the number. The effects of NMDA (5 nmol/5 microliters) can be blocked completely by APH (50 nmol/5 microliters). These results suggest an involvement of the NMDA receptor in experimental non-convulsive epilepsy, observed in the WAG/Rij model.

Genetics of spike-wave discharges in the electroencephalogram (EEG) of the WAG/Rij inbred rat strain: a classical mendelian crossbreeding study.

The WAG inbred strain might be an animal model for human absence epilepsy. To study the inheritance pattern of absence epilepsy, WAG rats were crossbred, in a classical Mendelian way, with inbred ACI rats which show no signs of epilepsy. In the parental strains, reciprocal F1 hybrids, F2, B1, and B2 generations, the number and duration of spikewave discharges were determined. One hundred percent of the F1 animals showed spike-wave discharges, while the percentages for the F2, B1 and B2 generations were 79, 95, and 37%, respectively. These results suggest that the occurrence of spike-wave discharges is determined by one gene with a dominant mode of inheritance. Cavallis least-squares fitting procedure suggested different genetic models for the two parameters (number and duration) during the two periods (dark and light). These results confirm our previous findings (Peeterset al., Behav. Genet. 20, 453–460, 1990) that a number of genes are involved in absence epilepsy. One dominant gene appears to determine the occurrence, however, while others manipulate the number and duration of epileptic phenomena during the two periods dark and light.

The WAG/Rij Rat Model for Nonconvulsive Absence Epilepsy: Involvement of NonNMDA Receptors

The involvement of AMPA and kainate receptors in nonconvulsive epilepsy was studied by intracerebroventricular injections of AMPA, GDEE, kainic acid and kynurenic acid in WAG/Rij rats. The WAG/Rij rat strain is recognized as an animal model for human absence epilepsy. EEG registrations showed that AMPA (0.1 pmol/5 microliters; 1 pmol/5 microliters; 10 pmol/5 microliters) dose-dependently increased the nonconvulsive absence epilepsy while GDEE (0.2 mumol/5 microliters; 1 mumol/5 microliters; 5 umol/5 microliters) caused a dose-dependent decrease. All effects of GDEE could be blocked by an inactive AMPA dosage. Kainic acid (0.01 nmol/5 microliters; 0.1 nmol/5 microliters; 0.15 nmol/5 microliters) had no effects on the nonconvulsive epilepsy but induced convulsions in the two highest dosages. Kynurenic acid (50 nmol/5 microliters; 100 nmol/5 microliters; 500 nmol/5 microliters) decreased dose-dependently the incidence of nonconvulsive epilepsy. The effect of kynurenic acid could be blocked by a nonconvulsive dosage of kainic acid. These results show that the AMPA and kainate receptor appear to be involved in nonconvulsive epilepsy. Furthermore, blockage of these two receptor subtypes led to an antiepileptic effect without inducing behavioural alterations. Therefore, selective AMPA and kainate receptor antagonists might be potent anti-epileptics.

CNQX, a new non-NMDA receptor antagonist, reduces spike wave discharges in the WAG/Rij rat model of absence epilepsy

The effects on seizures, EEG and behavior of the non-NMDA receptor antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), were studied in the WAG/Rij rat with absence epilepsy. Intracerebroventricular injections (10, 50, and 100 nmol/5 microliters CNQX) showed that CNQX decreases the number of spike wave discharges in a dose-dependent way. Coinjection of CNQX (100 nmol/5 microliters) and AMPA (0.1 pmol/5 microliters), kainic acid (0.01 nmol/5 microliters) or NMDA (50 pmol/5 microliters) attenuated the CNQX response, indicating that CNQX acts on both non-NMDA and NMDA receptors. The observed effects appear to be specific manipulations of the epilepsy not mediated by behavioral changes.

Effects of loreclezole on epileptic activity and on EEG and behaviour in rats with absence seizures

The antiepileptic profile of loreclezole, a new putative antiepileptic compound, has been determined in rats of the WAG/Rij strain, a genetic model of generalized absence epilepsy. In addition, the effects of 0, 5, 10 and 20 mg/kg loreclezole on the spectral content of the background EEG and on spontaneous behaviour of rats were investigated. Both the number of spike-wave discharges and their total duration dose-dependently decreased following administration of loreclezole. Furthermore, the behaviour of the animals was not markedly influenced and significant changes in the background EEG were not noticed after administration. These data suggest that the broad-spectrum antiepileptic loreclezole can be a valuable new drug in the treatment of absence epilepsy.

Effects of rearing and exposure condition upon the acquisition of phobic behaviour in cynomolgus monkeys

Young monkeys were confronted with a harmless novel object in their familiar home-cage environment. The effects of two rearing conditions (mother and surrogate mother) and two confrontation conditions [presence and absence of the (surrogate) mother] upon the acquisition of phobic behaviour were studied. Most surrogate-reared monkeys showed persistent maladaptive avoidance behaviour with respect to the object during tests, from 7 months of age onwards. Most mother-reared monkeys approached the object during tests taking food near it, from 7 months onwards. The confrontation condition had no effect upon behaviour with respect to the object. As no aversive conditioning procedures have been applied, merely presenting a harmless object appears to be enough to set off persistent avoidance in surrogate-reared monkeys. Further investigation of the origin of the phobic behaviour is interesting in view of developing animal models of human phobias of which no conditioning history is known.

Conditional control by midazolam and amphetamine in a rapid appetitive discrimination procedure

The present two experiments examined conditional control by midazolam and amphetamine cues in an appetitive discrimination procedure. In each of two experiments, male Wistar rats were subjected to a small number of two types of training sessions in a conditioning box. During one type of session, a stimulus was consistently followed by food in a magazine, whereas during the other type of session, this very same stimulus was followed by nothing. Groups of rats were injected with either midazolam (0.1 mg/kg, s.c.) or amphetamine (0.5 mg/kg, s.c.), prior to each food-reinforced session, and with saline prior to each food non-reinforced session. Other groups received the reverse treatment. Subsequent non-reinforced test session showed that, in both experiments, only the rats that had been food reinforced in a drug state displayed shorter magazine-response latencies in their previously reinforced than in their previously non-reinforced state, both prior to and during the stimulus. This finding was interpreted as reflecting the joint operation of unconditioned and conditioned drug effects, with the latter being based on occasion setting by the drug cues that was induced by the relatively short discrimination training procedure. The present results parallel those of previous aversive drug-discrimination experiments adopting a similar short discrimination procedure.

Diazepam and Ro 15-1788 increase absence epilepsy in WAG/Rij rats chronically exposed to diazepam.

The mechanisms underlying tolerance to benzodiazepines were investigated by injecting diazepam (5 mg/kg) twice daily for 23 days in WAG/Rij rats (an animal model for non-convulsive absence epilepsy). After this the rats received either the agonist, diazepam, or the antagonist, flumazenil (Ro 15-1788). EEG analyses showed that both compounds increased the amount of absence epilepsy-like phenomena. This suggests that repeated administration of diazepam moves the benzodiazepine receptor spectrum towards the inverse agonist end.