Biomedical subjects

W H Drinkenburg

Publications and source records attributed to W H Drinkenburg.

14 recordsLinked to original sources

PubMed1999

Haloperidol-induced within-session response decrement patterns and catalepsy in rats: behavioural dissociation.

The typical antipsychotic haloperidol is known to induce extra-pyramidal side-effects (EPS). Catalepsy in rats is generally regarded as a valid model for detecting the EPS liability of compounds in humans. Together with its antipsychotic and cataleptogenic actions, haloperidol causes an attenuation of instrumental responding which becomes larger in the course of a session: a within-session response decrement. The present study compared the time-course of haloperidol-induced catalepsy, measured by a bar test, to the haloperidol-induced within-session response decrements, measured by operant behaviour under a fixed ratio 10 schedule of reinforcement. Rats were trained to press a lever on a Fixed Ratio 10 schedule of food reinforcement during sessions of 15 min. When responding was stable, saline or haloperidol in 0.03 mg/kg, 0.1 mg/kg, or 0.3 mg/kg was administered intra-peritoneally either 30, 90 or 180 min prior to behavioural testing. The number of lever presses, food tray visits and latency to press the lever and to visit the food tray were analysed in five successive blocks of 3 min. Catalepsy was tested 30, 60, 90, 120, and 180 min. after injection, by placing a rat with its forepaws on a horizontal bar. The latency to remove both forepaws from the bar was scored. Within-session response decrements were present at 0.1 mg/kg and at 0.3 mg/kg, from 30 min after administration onward. At these doses, latency to press the lever was increased after 30 and 90 min, but not significantly after 180 min. Latency to visit the tray was affected only after 30 min, at 0.3 mg/kg. Haloperidol induced a dose-dependent increase in catalepsy from 60 min onwards, with maximal effect after 120 min. A dissociation between the time-course of occurrence of within-session response decrement and the cataleptogenic action of haloperidol, as well as between the latter and both latency measures, was found. Consequently, the present data suggest that within-session response decrements are not obviously caused by catalepsy-related impairments.

Animals↗

PubMed1998

Recognition memory in rats--I. Concepts and classification.

Recognition is the process by which a subject is aware that a stimulus has been previously experienced. It requires that the characteristics of events are perceived, discriminated, identified and then compared (matched) against a memory of the characteristics of previously experienced events. Understanding recognition memory, its underlying neuronal mechanisms, its dysfunction and alleviation of the latter by putative cognition enhancing drugs is a major research target and has triggered a wealth of animal studies. One of the most widely used animals for this purpose is the rat, and it is the rat's recognition memory which is the focus of this review. In this first part, concepts of recognition memory, stages of mnemonic processing and paradigms for the measurement of the rat's recognition memory will be discussed. In two subsequent articles (parts II and III) we will focus on the neuronal mechanisms underlying recognition memory in rats. Three major points arise from the comparison of paradigms that have in the past been used to assess recognition memory in rats. First, it should be realized that some tasks which, at face value, can all be considered to measure recognition memory in rats, may not assess recognition memory at all but may, for example, be based on recall rather than recognition. Second, it is evident that different types of recognition memory can be distinguished and that tasks differ in the type of recognition memory taxed. Some paradigms, for example, measure familiarity, whereas others assess recency. Furthermore, paradigms differ as to whether spatial stimuli or items are employed. Third, different processes, ranging from stimulus-response learning to the formation of concepts, may be involved to varying extent in different tasks. These are important considerations and question the predictive validity of the results obtained from studies examining, for example, the effects of putative cognition enhancing drugs.

Animals↗

PubMed1998

Recognition memory in rats--II. Neuroanatomical substrates.

A discussion of the neuroanatomical systems thought to be of importance for the mediation of recognition memory in the rat warrants consideration of different, but not necessarily exclusive concepts. An important concept is the hypothesis that a dichotomy in the neural systems mediating spatial and non-spatial (item) memory exists in the rat. We have adopted a model of recognition memory suggesting that information about previously encountered items is stored in a dynamic pattern of neural activity and not in a localized representation. These patterns are features of distributed neuronal networks and different networks may process different forms of recognition memory. Two parallel-distributed neuronal networks are proposed in the rat. Network 1 is essential for the processing of non-spatial/item recognition memory processes and incorporates the cortical association areas such as TE1, TE2 and TE3, the rhinal cortices, the mediodorsal thalamic nucleus and prefrontal cortical areas. Network 2 comprises the hippocampus, mamillary bodies, anterior thalamic nuclei and medial prefrontal areas, especially the prelimbic cortex, and is suggested to be pivotal for the processing of spatial recognition memory.

Animals↗

PubMed1998

Recognition memory in rats--III. Neurochemical substrates.

In the first part of three overviews on recognition memory in the rat, we discussed the tasks employed to study recognition memory. In the second part, we discussed the neuroanatomical systems thought to be of importance for the mediation of recognition memory in the rat. In particular, we delineated two parallel-distributed neuronal networks, one that is essential for the processing of non-spatial/item recognition memory processes and incorporates the cortical association areas such as TE1, TE2 and TE3, the rhinal cortices, the mediodorsal thalamic nucleus and prefrontal cortical areas (Network 1), the other comprising of the hippocampus, mamillary bodies, anterior thalamic nuclei and medial prefrontal areas (Network 2), suggested to be pivotal for the processing of spatial recognition memory. The next step will progress to the level of the neurotransmitters thought to be involved. Current data suggest that the majority of drugs have non-specific, i.e. delay-independent effects in tasks measuring recognition memory. This may be due to attentional, motivational or motoric changes. Alternatively, delay-independent effects may result from altered acquisition/encoding rather than from altered retention. Furthermore, the neurotransmitter systems affected by these drugs could be important as modulators rather than as mediators of recognition memory per se. It could, of course, also be the case that systemic treatment induces non-specific effects which overshadow any specific, delay-dependent, effect. This possibility receives support from lesion experiments (for example, of the septohippocampal cholinergic system) or studies employing local intracerebral infusion techniques. However, it is evident that those delay-dependent effects are relatively subtle and more readily seen in delayed response paradigms, which tax spatial recognition memory. One interpretation of these results could be that some neurotransmitter systems are more involved in spatial than in item recognition memory processes. However, performance in delayed response tasks can be aided by mediating strategies. Drugs or lesions can alter those strategies, which could equally explain some of the (delay-dependent) drug effects on delayed responding. Thus, it is evident that neither of the neurotransmitter systems reviewed (glutamate, GABA, acetylcholine, serotonin, dopamine and noradrenaline) can be viewed as being directly and exclusively concerned with storage/retention. Rather, our model of recognition memory suggests that information about previously encountered items is differentially processed by distinct neural networks and is not mediated by a single neurotransmitter type.

Animals↗

PubMed1998

Differential effects of non-REM and REM sleep on sensory gating in rats.

Sensory gating in rats can be measured with a double click paradigm. The diminished response towards the second click is a physiological manifestation of reduced sensory input. This physiological process seems to be disturbed in human psychoses. It is thought that gating, as measured with this paradigm, is a preattentive, involuntary phenomenon which is not modulated by attention. If this is indeed the case, than it is hypothesized that gating should not be modulated by non-REM sleep. In the present experiment pairs of clicks (500 ms interval) were presented during wakefulness, non-REM as well as REM sleep and cortical auditory evoked potentials (AEP's) were recorded in chronically implanted rats. Rather similar AEP's were found after the first and second stimulus. However, the amplitudes of the various components of the second AEP were smaller than those of the first AEP, suggesting a gated response. This was the case during all three levels of vigilance. The amplitudes of both AEP's showed the more often reported changes in amplitude during sleep and REM sleep. Clear differences were seen in gating: compared to wakefulness a decrease in gating was found during REM sleep while gating was unchanged during non-REM sleep. The latter outcome seems to confirm that gating in rats is indeed a preattentive process. Finally, results were discussed in terms of neuronal properties of thalamic relay cells and it is suggested that firing properties of thalamic relay cells are not involved in this type of sensory gating.

Acoustic Stimulation↗

PubMed1996

Effects of the GABAB antagonist CGP 35348 on sleep-wake states, behaviour, and spike-wave discharges in old rats.

The GABAB antagonist CGP 35348 was intraperitoneally given in doses of 100, 300, and 900 mg/kg to old rats. These rats were earlier chronically provided with EEG and EMG electrodes. Sleep recordings based on visual inspection of EEG and EMG recordings were made for 3 h post injection, and spontaneous behaviour in the recording cage was additionally observed. With 100 and 300 mg/kg, the drug produced an increase in the duration of REM sleep compared to the saline-injected control group. The REM sleep latency was correspondingly reduced. Non-REM sleep and total sleep duration increased and an s-shaped dose-response relationship was found. Explorative behaviour was diminished after injections with 100 and 300 mg/kg CGP 35348. The number and duration of spike-wave discharges were reduced after all doses of CGP 35348 and during all 3 recording hours. The latter outcomes confirm the strong suppressive action of this drug on spike-wave discharges; these effects have also been reported in models of absence epilepsy. The hypnotic properties and especially the increase in REM sleep after the administration of CGP 35348 deserve attention considering the paucity of drugs which facilitate REM sleep. The discovery of drugs promoting REM sleep might have theoretical as well as clinical consequences.

Aging↗

PubMed1995

Differential effects of midazolam and zolpidem on sleep-wake states and epileptic activity in WAG/Rij rats.

Hypnotic drugs are known to possess antiepileptic activity. Therefore, the effects of the benzodiazepine hypnotic midazolam (10 mg/kg) and the novel imidazopyridine hypnotic zolpidem (10 mg/kg) on sleep-wake states and on the number of spike-wave discharges were evaluated in WAG/Rij rats. Rats of this strain are considered to be a model for generalized absence epilepsy. Animals were implanted with chronic monopolar EEG electrodes and, after recovery from surgery, the EEG was recorded for 6 h during the dark period on 3 consecutive days. Sleep recordings were analyzed using Hjorth's parameters and number and duration of spike-wave discharges were visually determined. It was found that both drugs facilitated nonREM sleep at the cost of wakefulness. Both hypnotics also reduced the number and duration of spike-wave discharges. The initial decrease after midazolam, however, was followed by a rebound reflecting a poorer quality of vigilance expressed as an increase in spike-wave discharges. The strong antiabsence activity of zolpidem mimics that of midazolam and is well correlated with their equipotent hypnotic action and anticonvulsant effect in the isoniazid test.

Animals↗

PubMed1995

Sleep deprivation and spike-wave discharges in epileptic rats.

The effects of sleep deprivation were studied on the occurrence of spike-wave discharges in the electroencephalogram of rats of the epileptic WAG/Rij strain, a model for absence epilepsy. This was done before, during and after a period of 12 hours of near total sleep deprivation. A substantial increase in the number of spike-wave discharges was found during the first 4 hours of the deprivation period, whereas in the following deprivation hours epileptic activity returned to baseline values. Immediately after termination of deprivation, a decrease in the number of spike-wave discharges parallelled a rebound of rapid eye movement (REM) sleep and deep non-REM sleep. An initial increase in epileptic activity has also been reported during sleep deprivation of humans. This initial increase as well as the epileptogenic effects during the course of the sleep deprivation and during the recovery period after sleep deprivation can be interpreted in terms of changes in sleep-wake states. Although the epilepsy-provoking mechanisms are not yet understood, an explanation is suggested based on changes of transitions between sleep-wake states and shifts in level of synchronization.

Animals↗

PubMed1995

Carbon dioxide euthanasia in rats: oxygen supplementation minimizes signs of agitation and asphyxia.

This paper records the effects of carbon dioxide when used for euthanasia, on behaviour, electrical brain activity and heart rate in rats. Four different methods were used. Animals were placed in a box (a) that was completely filled with carbon dioxide; (b) into which carbon dioxide was streamed at a high flow rate; (c) into which carbon dioxide was streamed at a low flow rate and (d) into which a mixture of carbon dioxide and oxygen was streamed at a fast rate. It was found that the cessation of behaviour was associated with an aberrant pattern of electrical brain activity together with an abnormally low heart rate. The time to reach this point was shortest in those animals placed in the box filled with pure carbon dioxide, longer when carbon dioxide was introduced at a high rate into the box, longer still when oxygen was added to the carbon dioxide gas, and longest when carbon dioxide was streamed slowly into the box. In the condition with pure carbon dioxide, signs of behavioural agitation and asphyxia were seen. This was also true for the two conditions in which carbon dioxide streamed into the box, but to a lesser degree. These signs occurred when some degree of consciousness may still have been present in the animals. Signs of agitation and asphyxia were almost completely absent in the condition where oxygen was added to the carbon dioxide. These results not only demonstrate the usefulness of behavioural criteria next to electrophysiological indices, but also demonstrate that the negative effects of carbon dioxide euthanasia can be prevented by an additional supply of oxygen.

Animal Welfare↗

PubMed1993

Aberrant transients in the EEG of epileptic rats: a spectral analytical approach.

Aberrant transients in the cortical electroencephalogram of rats of the epileptic WAG/Rij strain were studied by means of spectral analysis. The EEG of rats of this strain contains, besides normal sleep spindles, high-voltage spiky phenomena, epileptic spike-wave discharges, and deviant intermediate stage. Spectral analysis of these transient phenomena shows that some features, like their peak frequency, are alike, but that they differ in other spectral characteristics, as in the first harmonic of the peak frequency and in the domain of the high frequencies. The results provide arguments for the view that spike-wave discharges might be considered as unique aberrant phenomena, presumably related but dissimilar to the high-voltage spiky phenomena and intermediate stage. Next to this, spectral analysis was used to study the intraphenomenal dynamics of spike-wave discharges. The peak frequency was found to decrease monotonously from about 10 Hz at the beginning of the spike-wave discharge to about 8 Hz at the end. Other spike-wave discharge frequency bands showed an intraphenomenal increase followed by a decrease. These time-variant EEG dynamics in spike-wave discharges might correlate with the cognitive disturbances during absence seizures in man.

Animals↗

PubMed1992

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.

Animals↗

PubMed1992

Genetic models of absence epilepsy, with emphasis on the WAG/Rij strain of rats.

In this review, the main characteristics of genetic models of absence epilepsy, in particular with respect to WAG/Rij rats, are presented. Genetic models are important and relevant, since evidence exists that these models mimic spontaneously occurring human epilepsy more than models in which epilepsy is artificially induced. Genetic models can be divided into models in which seizures are elicited and into those in which epilepsy appears without any sensory stimulation. The majority of genetic models show that absence type of epilepsy; during the last few years, we and others have noticed that rats of various strains exhibit spontaneously occurring spike-wave discharges in the EEG. Among the strains highly affected is the WAG/Rij strain, which is a fully inbred strain. Individuals are homozygous and because of this property, genetic studies are meaningful. Electrophysiological studies have indicated that abnormal discharges in the cortical EEG are generalized and that the hippocampus is not involved. Parts of the thalamus, together with the thalamic reticular nucleus, apparently act as a pacemaker for the abnormal discharges. There is a circadian modulation in the number of spike-wave discharges. Discharges mainly occur during intermediate levels of vigilance such as passive wakefulness and light slow-wave sleep and at transitions of sleep states. Pharmacological studies with clinically effective antiepileptic drugs have shown a close agreement in seizure response between man and rat. Studies with new compounds have emphasized the role of the GABAergic and glutamatergic system in this type of epilepsy. Particularly striking is the role of the GABAergic system. GABA agonists enhance and GABA antagonists reduce the occurrence of spike-wave discharges, which deviates from the effects of GABAergic drugs in non-convulsive epilepsy. Even more striking is the role of the benzodiazepines, generally seen as GABA agonists; these drugs do not act as such in absence epilepsy since they reduce spike-wave discharges. Also good evidence for an involvement of other neurotransmitters such as noradrenaline, dopamine and opioid peptides exists in absence epilepsy. Genetic data obtained from the WAG/Rij model for absence epilepsy show a relatively simple pattern of inheritance with one gene determining whether an individual is epileptic or not, and with other genes regulating the number and duration of seizures. This is in good agreement with the more restricted human data. Cognitive studies have shown two important features of epilepsy in the WAG/Rij strain: modulation of the number of spike-wave discharges by mental or physical activity and on the other hand, the disruption of cognitive activity by spike-wave discharges.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1991

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.

Action Potentials↗

PubMed1991

Absence epilepsy and the level of vigilance in rats of the WAG/Rij strain.

In man, a relationship exists between sleep-wake states and absence epilepsy. During wakefulness, spike-wave discharges predominantly occur when the level of vigilance is not high, while during sleep they have a preference to occur during slow-wave sleep. During this latter type of sleep, spike-wave discharges prevail in periods where slow-wave sleep is light. In a series of experiments, the WAG/Rij rat model for absence epilepsy was characterized with respect to the relationships between the level of vigilance, sleep-wake states and the occurrence of spike-wave discharges. In the first experiment, continuous recordings were made for a period of 48 h and a clear circadian rhythm was established for the number of spike-wave discharges. A maximum appeared during the middle of the dark period of the rat, whereas a minimum was detected directly after the onset of the light period, the time period during which deep slow-wave sleep predominates. The relationship of spike-wave discharges with states of vigilance was elaborated in a second study. Spike-wave discharges were mainly found during light slow-wave sleep, during passive wakefulness and in transition phases from sleep to wakefulness. During REM sleep no spike-wave discharges were found. In the last three experiments, the level of alertness was enhanced by various procedures as photostimulation, a learning task and deprivation of REM sleep. In all cases, an increase of alertness decreased the amount of epilepsy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗