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Biomedical subjects

G van Luijtelaar

Publications and source records attributed to G van Luijtelaar.

16 recordsLinked to original sources
PubMed2004

The influence of strain and housing on two types of spike-wave discharges in rats.

WAG/Rij rats, a genetic model of absence epilepsy, show two types of spike-wave discharges (Type 1 and Type 2) in their EEG activity. The large interindividual variation in the expression of the phenotypes (number and mean duration of spike-wave discharges) suggests that as well as genetic, environmental factors also play a role. The aim of our study was to establish effects of strain and housing on the incidence and expression of both types of paroxysms. Therefore, WAG/Rij and ACI rats were housed from weaning in either an enriched or impoverished environment for 60 days. At three months of age the EEG of the rats was recorded for four hours to examine the effects of strain and housing on the incidence and expression of the two types of paroxysms. Generally, enriched housing led to worsening of Type 1 and Type 2 spike-wave discharges (SWD). However, the number of affected rats and the expression (number and mean duration) of Type 1 and Type 2 spike-wave discharges were differently influenced by strain and housing. This suggests that Type 1 and Type 2 spike-wave discharges are independent phenomena and that number and mean duration of these paroxysms are controlled by different mechanisms. Finally, the worsening of absence seizures after enrichment is different from what has been found for convulsive seizures.

Animals↗
PubMed2002

Causes and consequences of pathogenic processes in evolution: implications from experimental epilepsy in animals.

Examples from experimental epilepsy in animals are used to illustrate the view that a crucial role of the transfer of mechanisms from compensatory into pathogenic (e.g. lethal ones in the course of a disease), is played by the power of pathologic stimuli. In the genesis of epilepsy it is suggested that a critical increase of endogenous factors may underlie the conversion of the absence form of epilepsy into a generalized self-supporting form. The ability to precipitate endogenous self-augmenting mechanisms of diseases may have increased in the course of evolution. The lethal result of a serious pathogenic process leads to the suggestion that organisms cope with the disease by dying. This prevents spreading of the putative infectious disease within the population. This mechanism of disease aggravation could play a role in the survival of the species and in further evolutionary progress. This may explain why certain species may have survived in evolution and supports the theory of synthetic evolution.

Animals↗
PubMed2001

Neural correlates of sensory gating in the rat: decreased Fos induction in the lateral septum.

In the P(50) gating or conditioning-testing paradigm in the rat, two identical click stimuli are presented with an inter-click interval of 500 ms. The reaction towards the second click, as measured with evoked potentials, is reduced in respect to that towards the first click; this phenomenon is called sensory gating. In the present experiments, the inter-click interval was varied systematically and auditory evoked potentials were measured. Sensory gating was found to occur only at intervals between 500 and 1000 ms, but not at longer intervals. Fos immunohistochemistry was then performed using two groups of rats exposed to double clicks: the inter-click interval was 500 ms in the experimental group and 2500 ms in the control group. Fos induction was analyzed in selected brain structures. In the auditory pathways, Fos-immunoreactive neurons were found in both groups of rats in the inferior colliculus and medial geniculate body. Fos-immunoreactive cells were also examined in the septum and hippocampus. In the ventral part of the lateral septal nucleus, the labeled neurons were significantly fewer in the experimental animals compared to the control group. Smaller and non-significant quantitative differences of Fos-positive neurons were documented in the medial septum and hippocampal CA1 region. These data point out a selective decrease in the lateral septum of Fos induced by auditory sensory gating, and suggest an involvement of this structure, and possibly of other parts of the septo-hippocampal system, in sensory gating mechanisms. The results might be relevant for theories on sensory gating deficits in schizophrenia.

Acoustic Stimulation↗
PubMed2001

The role of hippocampal theta activity in sensory gating in the rat.

Sensory gating is defined as a decreased reaction on the second click, measured as evoked potentials (EP) within a double click paradigm. Recently, it was established that gating in rats was decreased during REM sleep compared to wakefulness and non-REM sleep. REM sleep in the rat is characterized by hippocampal theta rhythm. Therefore, it was investigated whether sensory gating would also be diminished during other states with hippocampal theta. Twelve Wistar rats were implanted with hippocampal electrodes and exposed to double clicks during passive wakefulness, REM sleep, and activity (voluntary movements and walking on a moving belt). Gating was examined by use of the amplitudes of the EPs in reaction to the first conditioned amplitude (CAMP) and second click test amplitude (TAMP), as well as two gating parameters (C-T score and T/C ratio). Except passive wakefulness all behavioral conditions were accompanied by hippocampal theta. Normal gating was always found, except during REM sleep. The CAMP was than lower than during passive wakefulness. Gating was less disturbed during behavioral activity. Negative correlations were found between the percentage theta power on the one side and the CAMP, respectively, the C-T score, on the other. The correlation between the percentage theta power and the T/C ratio was also significant. It is concluded that the presence of hippocampal theta is not a sufficient condition to cause disturbances in auditory sensory gating. Behavioral states that accompany theta activity, however, tend to affect the CAMP. The decrease in gating found during REM sleep cannot be easily related to well-known neurochemical and pharmacological data.

Animals↗
PubMed2001

The ovarian hormones and absence epilepsy: a long-term EEG study and pharmacological effects in a genetic absence epilepsy model.

In the first experiment, the relationship between the phase of the estrous cycle and the number of spontaneously occurring spike-wave discharges was investigated in WAG/Rij rats, a model for generalized absence epilepsy. The electroencephalogram (EEG) was continuously recorded for 96 h in eight rats chronically equipped with cortical EEG electrodes. A circadian pattern emerged for the number of spike-wave discharges: a nadir during the first hours of the light period, and an acrophase during the first hours of the dark period. This daily maximum was increased at proestrus day compared with the other days of the cycle, when the plasma level of progesterone is enhanced specifically at these hours of this day. This suggests that progesterone enhances spike-wave discharges. There was no difference in the first few hours of the light period in the number of spike-wave discharges between proestrus and the three other days, suggesting that estradiol has no effect on spike-wave discharges. In the second study, the effects of the systemic administration of progesterone and 17 beta-estradiol on spike-wave discharges and spontaneous behavior were investigated. It was shown that progesterone (20 and 30 mg/kg) but not estradiol (0.17-1.5 mg/kg) increased the number and total duration of spike-wave discharges. On the other hand, injection of RU 38486 (10 and 30 mg/kg), an antagonist of intracellular progesterone receptors, had no effect on spike-wave discharges and did not block the stimulatory effect of progesterone. The antagonist of 17 beta-estradiol tamoxifen (1 and 3 mg/kg) did not evoke alterations in the number or duration of spike-wave discharges. Our results indicate that progesterone aggravates spike-wave discharges, but is not mediated through intracellular receptors. Since progesterone is rapidly metabolized in the brain to the positive modulator of GABA(A) receptor allopregnanolone, which increases spike-wave discharges in WAG/Rij rats, it is possible that the epileptiformic effects of progesterone are mediated through this metabolite.

Animals↗
PubMed2000

Opposite effects of T- and L-type Ca(2+) channels blockers in generalized absence epilepsy.

The role of the T-type Ca(2+) channel blocker, ethosuximide, the L-type Ca(2+) channel blocker, nimodipine and L-type Ca(2+) channel opener, BAY K8644 (1,4 Dihydro-2, 6-dimethyl-5-nitro-4-[trifluoromethyl)-phenyl]-3-pyridine carboxylic acid methyl ester), was investigated on spike-wave discharges in WAG/Rij rats. This strain is considered as a genetic model for generalized absence epilepsy. A dose-dependent decrease in the number of spike-wave discharges was found after i.c.v. ethosuximide, an increase after i.p. nimodipine and a decrease after i.c.v. BAY K8644. BAY K8644 was also able to antagonise the effects of nimodipine. Preliminary data were obtained with two conotoxins, MVIIC and GVIA, which block P/Q-type and N-type Ca(2+) channels, respectively. Only after i.c.v. administration of omega-conotoxin GVIA were the number and duration of spike-wave discharges reduced, but animals showed knock-out lying. The latter suggests behavioural or toxic effects and that the decrease in spike-wave activity cannot unequivocally be attributed to blockade of N-type Ca(2+) channels. It can be concluded that T- and L-type Ca(2+) channel blockers show opposite effects on spike-wave discharges. Furthermore, these effects are difficult to explain in terms of a model for spindle burst activity in thalamic relay cells proposed by McCormick and Bal [Sleep and arousal: thalamocortical mechanisms.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1999

Sensory gating in rats: lack of correlation between auditory evoked potential gating and prepulse inhibition.

This study was designed to evaluate the possible similarities between two paradigms designed to measure sensory gating: (1) an auditory evoked potential (AEP), called the P50 gating paradigm; and (2) an acoustic startle (ASR), called the prepulse inhibition paradigm. These paradigms show a number of methodological, pharmacological, and neurobiological similarities, and they are both disturbed in patients with schizophrenia. In the first of three experiments, the AEP gating and the ASR gating were measured in rats. Although both AEP and ASR gating could readily be obtained, there appeared to be no correlation between the performance in these two paradigms. This lack of correlation was confirmed using a factor analytical approach, where the AEP gating and the ASR gating parameters were found to load on different factors. In the second experiment, the interstimulus interval in the ASR paradigm was increased to 500 ms (identical to the interstimulus interval of the AEP gating paradigm). This increase reduced the degree of ASR gating, although some gating could still be obtained. Again no correlation was found between AEP and ASR gating, and this was again confirmed by the factorial analysis. In the final experiment, the effects of the dopamine D2/3 agonist 7-OHDPAT were evaluated in both paradigms. This selective agonist dose dependently reduced ASR gating but had no effect on AEP gating. Together, these data strongly suggest that AEP and ASR gating measure two different aspects of information processing and indicate that both paradigms may be important for investigating the neurobiological disturbances observed in patients with psychoses.

Animals↗
PubMed1998

Anatomical and functional aspects of mu opioid receptors in epileptic WAG/Rij rats.

Involvement of opioid systems in the pathogenesis of absence epilepsy has been postulated. However, the role of the mu opioid receptor has not been fully elucidated as yet. In the present study the role of this receptor in absence epilepsy was investigated autoradiographically and pharmacologically. The density of mu opioid receptors in discrete brain areas was quantified in WAG/Rij rats, which are regarded as a genetic model of primarily generalized absence epilepsy and in three control groups of non-epileptic rats. The autoradiographic study showed an abundance of mu opioid receptors (labelled with [3H]DAMGO) in the structures involved in generation and propagation of spike-wave discharges, such as the thalamus, cortex and striatum. A significant decrease in the mu receptor density was found only in the frontal cortex of epileptic WAG/Rij rats. In the pharmacological study, the effect of mu opioid receptor activation in different brain structures of WAG/Rij rats on the number of complexes of spike-wave discharges was investigated. DAMGO (0.02 and 0.07 microg/0.5 microl) was bilaterally injected into the thalamus, striatum and frontal cortex. DAMGO resulted in a dose-related increase in the number of spike-wave discharges after intracortical and intrastriatal administration by approximately 200-300% and after intrathalamic administration by approximately 500%. The injection of DAMGO into those structures had no significant effect of any kind on the behavior measured, except for passive behavior which was reduced after intrastriatal injection. The high density of mu opioid receptors in the areas involved in the genesis of spike-wave discharges, as well as the highest responsiveness of thalamic mu opioid receptors to the epileptogenic effects of DAMGO, suggest involvement of mu receptors in the genesis of spike-wave discharges.

Analgesics, Opioid↗
PubMed1997

Effects of the tranquillizer diazepam and the stimulant methylphenidate on alertness and memory.

Effects of alertness and memory of a single dose of diazepam (10 mg) and the central stimulant methylphenidate (20 mg) were studied in healthy volunteers. It was questioned whether opposite effects of diazepam and methylphenidate are not only observed with respect to alertness but also with respect to memory. It was also questioned whether the two drugs equally affect the first (primacy) and last (recency) items in both the immediate and delayed recall of newly learned words. The experiment was performed in a double-blind, placebo-controlled way. 12 subjects were exposed to a subjective alertness scale and a verbal memory test: a 15-word test. Subjective alertness was found to be decreased after diazepam and increased after methylphenidate. Anterograde amnesia was found after diazepam in the memory test. More specifically, the primacy but not the recency effect was reduced during the immediate recall and both were reduced in the delayed recall. methylphenidate had no effect on memory, however a ceiling effect might have obscured a putative drug effect. The results of a second experiment excluded this possibility. In all, the data demonstrate opposite effects of the two drugs on subjective alertness, suggesting opposite effects on vigilance. Opposite effects on memory were not established. This demonstrates that changes in alertness do not run in parallel with changes in memory. A scatter diagram, however, suggests a small effect of alertness on immediate recall. The effects of diazepam were also discussed in terms of the Atkinson and Shiffrin memory theory and it seems that diminished rehearsal processes are one of the key factors in explaining diazepam-induced amnesia.

Adult↗
PubMed1995

Kappa opioid receptor agonists suppress absence seizures in WAG/Rij rats.

Involvement of the kappa opioid receptor in the regulation of epileptic activity was studied in WAG/Rij rats, a genetic model of absence epilepsy. I.c.v. administration of the kappa agonists U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide), U69,593 (5 alpha, 7 alpha, 8 beta)-(-)-N-methyl-(1-pyrrolidinyl)-1- oxaspiro(4,5)dec-8-yl)benzeneacetamide) or PD117,302 ((+/-)-trans-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzo[b]thiophene-4-acetamide), 50 and 150 micrograms/5 microliter each, dose-dependently decreased the number and mean duration of spike wave discharges (SWD). Peripheral administration of U50,488H (10 and 30 mg/kg s.c.) also attenuated the seizure activity in this model. The specific kappa opioid receptor antagonist nor-binaltorphimine (Nor-BNI, 10 micrograms/5 microliters i.c.v., 18 h before EEG registration) moderately increased the number of SWD, which suggests that endogenous opioids acting through kappa receptors may tonically inhibit the seizure activity in these rats. In addition, the enhancement of an absence-like seizure activity induced by the specific mu opioid receptor agonist D-Ala2-N-methyl-Phe4-Gly5-ol-enkephalin (DAMGO, 0.7 microgram/5 microliters i.c.v.) was also attenuated in rats pretreated with U50,488H, U69,593 or PD117,302. These data indicate that activation of the kappa opioid receptor exerts an inhibitory effect on absence-like seizure activity in WAG/Rij rats.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1995

Impairment of intracortical GABAergic inhibition in a rat model of absence epilepsy.

The WAG/Rij rat strain is characterized in its EEG by the manifestation of spike-wave discharges which resemble in their spontaneous appearance and pharmacological sensitivity the absence epilepsy observed in humans. In order to test the hypothesis whether cellular intrinsic membrane and/or synaptic network properties in the neocortex are modified in this form of epilepsy, we analyzed with extra- and intracellular recording techniques the functional status of neocortical slices obtained from adult epileptic WAG/Rij rats and compared them with the data acquired from non-epileptic control Wistar rats. Intrinsic membrane properties, like resting membrane potential, neuronal input resistance and basic cellular firing characteristics, did not differ between these two strains. However, the analysis of extra- and intracellularly recorded synaptic responses revealed an intracortical hyperexcitability which was accompanied by a significant reduction in the efficiency of GABAergic inhibition. Our data indicate that the imbalance between intracortical excitatory and inhibitory mechanisms may at least contribute to the expression and augmentation of spike-wave discharges in epileptic WAG/Rij rats.

Animals↗
PubMed1995

Effects of diazepam and buspirone on reaction time of saccadic eye movements.

Effects of the anxiolytic drugs diazepam and buspirone were studied on the reaction time of saccadic eye movements. The study was performed with 8 healthy volunteers in a double-blind, placebo-controlled way. The purpose was to investigate the putative drug effects on the first step of an attention shifting task: the disengagement of attention. Saccadic reaction time was measured in two conditions: the 'gap' and the 'overlap' condition. In the first condition a delay is present between the offset of a fixation spot and the onset of a target, while in the second condition the offset of the spot is overlapped by the onset of the target. Clear differences in saccadic reaction time in the expected direction were found between the two conditions, with longer reaction times of saccadic eye movements in the overlap condition. The nonsedative anxiolytic buspirone in a dose of 5 mg had no significant effects on saccadic reaction times, while clear effects of diazepam in a dose of 5 mg were established. Diazepam slowed down saccadic reaction times, reduced the number of fast saccades and facilitated the number of slow saccades. However, the effects induced by this drug were identical for the two conditions. The latter result implies that the disengagement of attention is not selectively disrupted by diazepam. Perhaps, the action of diazepam is expressed in other attention factors, such as in shifting attention or in the reengagement of attention. A slowing down of these processes by the vigilance-lowering properties of diazepam might be the cause of the prolonged latencies. The increased latencies of saccadic eye movements induced by a low dose of diazepam may have practical implications.

Adult↗
PubMed1992

Cognition and vigilance: differential effects of diazepam and buspirone on memory and psychomotor performance.

Effects of a single dose of the anxiolytic buspirone (15 mg) on memory and psychomotor performance were studied in healthy volunteers and compared to those of the classic benzodiazepine anxiolytic diazepam (15 mg). The study was performed in a double-blind, placebo-controlled way. Three groups of 12 subjects were exposed to an extended test battery before and after intake of drug or placebo. Next to this, an evaluation session took place 1 week later. Immediately after intake, diazepam exerted major effects on memory, impaired psychomotor performance and decreased alertness. In particular, long-term memory had deteriorated, which was interpreted as anterograde amnesia. One week later, more items were recalled from the predrug session compared to the number of items from the postdrug session; this was interpreted as retrograde facilitation. After intake of buspirone, there were no effects of alertness and vigilance, on psychomotor performance and on memory. One week later, a small memory decrement was noticed for verbal material, which was considered as a sign of anterograde amnesia. These results indicate that effects of anxiolytics on memory can be more easily demonstrated 1 week later than immediately after drug intake and, furthermore, that the disruptive effects of diazepam outweight the small effects of buspirone. Finally, it was established that the effects of diazepam on cognition might be mediated by its effects on alertness and vigilance and that cognitive effects are not related to the anxiolytic properties of the drug.

Adult↗
PubMed1991

Prospective and retrospective time estimation.

30 students, when performing a task that required listening to 19 sentences for 150 sec., overestimated the duration of the task less in the prospective condition than in the retrospective one (46 sec. vs 85 sec.).

Adult↗
PubMedDate not supplied

Protective effects of TRH and its analogues in chemical and genetic models of seizures.

TRH shows strong influence on neuronal excitability and may participate in the regulation of seizures. We investigated the effect of TRH and its stable analogues on seizures induced by intravenous (i.v.) infusion of pentetrazole in rats. The data showed that i.v. administration of TRH (10 and 20 mg/kg), RGH-2202 (0.1 mg/kg) and Z-p-Glu-His-Pro-NH2 (10 mg/kg) increased threshold for pentetrazole-induced clonic seizures, but did not affect the tonic ones. Another stable analogue of TRH, 1p-Glu-Tyr-Pro-NH2 (0.1-10 mg/kg), had no effect on pentetrazole-induced seizures. In further study, effects of TRH and RGH-2202 were examined in WAG/Rij rats, a genetic model of absence epilepsy. TRH (25 and 50 micrograms i.c.v.) decreased dose-dependently the number and mean duration of spike-wave discharges in cortical EEG of WAG/Rij rats at 90 and 120 min after the peptide administration. On the other hand, RGH-2202 (1 microgram i.c.v.) significantly decreased only the number of spike-wave discharges at 60 min post-injection. These results confirm that TRH and some of its analogues have moderate antiepileptic activity.

Action Potentials↗