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Biomedical subjects

M Vergnes

Publications and source records attributed to M Vergnes.

At least 55 records · Page 3Linked to original sources
PubMed1993

Cerebral energy metabolism in rats with genetic absence epilepsy is not correlated with the pharmacological increase or suppression of spike-wave discharges.

The quantitative [14C]2-deoxyglucose (2-DG) autoradiographic method was applied to measure the effects of pharmacological agents on local cerebral metabolic rates of glucose (LCMRglcs) in a selected strain of Genetic Absence Epilepsy Rats from Strasbourg (GAERS). In a previous study, we have shown that GAERS display an overall significant increase of LCMRglc compared to non-epileptic rats from a selected strain. To further characterize the metabolic responses in GAERS, we measured the effects of drugs aggravating or suppressing absences. The animals were divided into 4 groups, i.e. 2 non-epileptic control groups and 2 GAERS groups. Ten min before the initiation of the 2-DG procedure, both non-epileptic control and epileptic rats received an injection of the same amount of the pharmacological agent, either haloperidol (2 mg/kg) or ethosuximide (200 mg/kg). In the presence of haloperidol, GAERS exhibited almost continuous spike-wave discharges; however, the difference in energy metabolism between GAERS and non-epileptic control rats was abolished and LCMRglcs were similar in all structures of both groups of animals. In GAERS treated with ethosuximide, spike-wave discharges were totally suppressed, whereas rates of energy metabolism remained higher by 31-72% in all structures of epileptic rats compared to their corresponding non-epileptic controls. These data demonstrate a lack of correlation between the occurrence of spike-wave discharges and LCMRglcs and are in favor of normal or decreased ictal metabolism and of increased interictal glucose utilization by the brain in rats with absence epilepsy.

Action Potentials↗
PubMed1993

Effects of cholinergic drugs on genetic absence seizures in rats.

Wistar rats of a selected strain show spontaneous generalized non-convulsive seizures with bilateral synchronous spike-wave discharges on the cortical electroencephalograph (EEG). The 7 to 9 c/s spike-wave discharges occur predominantly in waking states of inactivity. The effects of cholinergic drugs on the cumulated duration of spike-wave discharges were investigated in this rat model of absence epilepsy. I.p. injections of drugs which potentiate cholinergic neurotransmission, namely the acetylcholinesterase inhibitor, physostigmine (0.1-0.5 mg/kg), the muscarinic receptor agonists, oxotremorine (0.25-1 mg/kg) and pilocarpine (0.125-2 mg/kg), and the nicotinic receptor agonist, nicotine (0.062-2 mg/kg), suppressed discharges in a dose-dependent manner and induced an arousal-like cortical EEG. The muscarinic receptor antagonist, scopolamine, increased the spike-wave discharges at doses below 0.05 mg/kg; at higher doses (0.05-1 mg/kg) it decreased discharges and induced a sleep-like EEG. The nicotinic receptor antagonist, mecamylamine (0.5-6 mg/kg), had no effect on spike-wave discharges or the EEG. These results suggest that cholinergic activity accounts for the preferential occurrence of absence seizures in states of reduced arousal.

Animals↗
PubMed1993

22-28 kHz ultrasonic vocalizations associated with defensive reactions in male rats do not result from fear or aversion.

This study was carried out to determine whether 22-28 kHz vocalizations emitted during intermale interactions in adult rats were related with a state of fear, aversion or resulted from painful stimulation. Vocalizations in the 22-28 kHz range were measured in male rats during non-aggressive and aggressive social interactions; when given foot shock with a partner; during non-aggressive social interactions after an injection of (i) acetic acid (1%, IP); (ii) pentylenetetrazol (20-30 mg/kg, IP) and (iii) lithium chloride (63.8 mg/kg, IP). Ultrasonic vocalizations were consistantly detected in all rats while the animals displayed defensive or submissive postures when tested as intruders confronted with offensive residents or when administered foot shocks. Only occasional vocalizations were emitted, even in the presence of a partner, when the animals had received other painful or aversive treatments. These data support the hypothesis that 22-28 kHz vocalizations during intermale interactions are associated with defensive postures and are not the consequence of a state of fear or aversion.

Acetates↗
PubMed1993

GABAA receptor impairment in the genetic absence epilepsy rats from Strasbourg (GAERS): an immunocytochemical and receptor binding autoradiographic study.

Some aspects of the GABA and cholinergic systems have been investigated in the cortex and thalamus of GAERS Wistar rats, a model of petit-mal epilepsy, and in a non-epileptic control strain. GABA and its synthetic enzyme, glutamic acid decarboxylase (GAD), were located by immunocytochemistry; the GABAA receptors were evaluated by autoradiography of GABA-enhanced 3H-flunitrazepam binding and by immunocytochemistry using specific antibodies against the beta 2-beta 3 subunits of GABAA receptor protein. GABA and GAD immunocytochemistry did not show up any difference in density or distribution of immunoreactive elements (fibers, terminals and neurons) between epileptic and control animals, but autoradiographic and immunocytochemical studies showed a decreased enhancement of 3H-flunitrazepam binding and of beta 2-beta 3 subunits of GABAA receptor in the sensorimotor cortex and anterior thalamic areas of the epileptic strain. No differences were found in benzodiazepine receptors in the two strains. GABAB receptors were measured as 3H-baclofen binding in a crude synaptic membrane preparation and there was no difference between epileptic and control animals. Choline acetyltransferase, the synthetic enzyme for acetylcholine, and muscarinic receptor subtypes (M1 and M2), visualized respectively by an immunocytochemical procedure and binding autoradiography, did not differ in epileptic and normal rats. The data suggest an impairment of the 'GABAA system' in restricted brain regions of epileptic rats, due to a reduction of receptor beta 2-beta 3 subunits and coupling to benzodiazepine receptors despite the normal synthesis and location of the neurotransmitter.

Acetylcholine↗
PubMed1993

Reciprocal positive transfer between kindling of audiogenic seizures and electrical kindling of inferior colliculus.

The behavioral and EEG concomitants of kindling produced by daily electrical stimulation of the inferior colliculus have been recorded in three series of Wistar rats: (1) non epileptic controls (NE), (2) rats susceptible to audiogenic seizures (AS), (3) acoustically susceptible rats with prior kindling of audiogenic seizures by repeated sound exposure (KAS). Repeated collicular stimulation produced behavioral and EEG changes which were similar in the AS and the NE rats. The tonic seizure without cortical discharges elicited by the first stimulation progressively changed into tonic-clonic seizures with sustained cortical EEG discharges after more than 20 stimulations. In the KAS group, the electrical collicular kindling was clearly accelerated: kindled tonic-clonic seizures and their EEG discharges already occurred after one to five electrical stimulations. Similarly, after completion of electrical collicular kindling in AS, sound stimulations immediately induced characteristic kindled audiogenic seizures. The immediate reciprocal positive transfer observed between kindling of audiogenic seizures and kindling of seizures induced by electrical stimulation of the inferior colliculus suggests that kindling of these two brain-stem seizures involves similar structures and mechanisms.

Acoustic Stimulation↗
PubMed1992

The GABAA receptor complex in experimental absence seizures in rat: an autoradiographic study.

The regional distribution of radioactive ligand binding for different receptors of the gamma-aminobutyric acid A (GABAA)-benzodiazepine-picrotoxin chloride channel complex was measured on tissue section by autoradiography in brains taken from a genetic strain of Wistar rats with spontaneous absence-like seizures, the genetic absence epilepsy rats from Strasbourg (GAERS), and a control colony. The ligands employed included [3H]muscimol for high affinity GABA agonists sites; [3H]SR 95531 for the low-affinity GABA sites; [3H]flunitrazepam for the benzodiazepine sites; and [35S]t-butyl bicyclophosphorothionate (TBPS) for the picrotoxin site. There was no significant change between GAERS and control animals in [3H]flunitrazepam and [35S]TBPS binding. However, there was significantly decreased [3H]muscimol and [3H]SR 95531 binding in the CA2 region of the hippocampus of the GAERS. This was due to a decrease in Bmax of both [3H]muscimol and [3H]SR 95531 binding in the epileptic strain.

Animals↗
PubMed1992

Dorsal tegmentum kindling in rats.

Electrical stimulations were applied daily for 40 days to the dorsal tegmentum in 9 rats through chronically implanted bipolar electrodes. The intensity of current (2 s trains of 50 Hz, 1 ms monophasic square waves) necessary to trigger a full tonic seizure was determined and applied for all further stimulations. Initial stimulations induced a tonic seizure with a low voltage fast electrocorticographic activity. After repeated stimulations, high amplitude spike and wave discharges developed over the cortex, their duration exceeding 50 s at the 40th stimulation. Simultaneously, the tonic seizures evolved into tonic-clonic fits with bilateral myoclonias following the tonic phase. These EEG and behavioral modifications persisted for 30 days after the last stimulus. These results demonstrate that kindling may be obtained from brainstem structures.

Animals↗
PubMed1992

Mapping of cerebral energy metabolism in rats with genetic generalized nonconvulsive epilepsy.

The quantitative 2-[14C]deoxyglucose autoradiographic method was applied to measure local cerebral metabolic rates of glucose (LCMRglc) in a model of genetic petit-mal-like seizures in a strain of Wistar rats. During the experimental period, epileptic rats exhibited synchronous spike-and-wave discharges, whereas the EEG pattern of control animals was normal. Overall, LCMRglc was consistently higher in epileptic rats than in the non-epileptic controls. The increase in LCMRglc was widespread and concerned all cerebral functional systems studied, whether they exhibit spike-and-wave discharges (neocortex and thalamus), or not (limbic system). These results are in good accordance with positron-emission tomography measurements in humans with typical childhood absence epilepsy. There appears to be a lack of anatomical correlation between areas demonstrating hypermetabolism and areas where spike-and-wave discharges are recorded. The administration of 200 mg/kg ethosuximide completely suppressed spike-and-wave discharges in epileptic rats and did not change the EEG pattern in controls. However, LCMRglc were increased to the same extent over control values in epileptic rats whether they were injected with ethosuximide or untreated. By contrast, when epileptic rats were given 2 mg/kg haloperidol, the frequency and the length of spike-and-wave discharges increased, inducing almost a permanent petit-mal status epilepticus. Haloperidol did not change EEG pattern in controls. In haloperidol-treated epileptic rats, LCMRglc decreased to levels comparable to those measured in untreated control rats. In the presence of haloperidol, LCMRglc were similar in both control and epileptic rats. Thus, the diffuse increase in cerebral energy metabolism in epileptic rats as compared to controls is not directly related to the occurrence of spike-and-wave discharges, and may rather be associated with inhibitory mechanisms involved in their termination and suppression, as well as their spread to limbic and motor structures.

Animals↗
PubMed1992

Experimental absence seizures: potential role of gamma-hydroxybutyric acid and GABAB receptors.

We have investigated whether the pathogenesis of spontaneous generalized non-convulsive seizures in rats with genetic absence epilepsy is due to an increase in the brain levels of gamma-hydroxybutyric acid (GHB) or in the rate of its synthesis. Concentrations of GHB or of its precursor gamma-butyrolactone (GBL) were measured with a new GC/MS technique which allows the simultaneous assessment of GHB and GBL. The rate of GHB synthesis was estimated from the increase in GHB levels after inhibition of its catabolism with valproate. The results of this study do not indicate significant differences in GHB or GBL levels, or in their rates of synthesis in rats showing spike-and-wave discharges (SWD) as compared to rats without SWD. Binding data indicate that GHB, but not GBL, has a selective, although weak affinity for GABAB receptors (IC50 = 150 microM). Similar IC50 values were observed in membranes prepared from rats showing SWD and from control rats. The average GHB brain levels of 2.12 +/- 0.23 nmol/g measured in the cortex and of 4.28 +/- 0.90 nmol/g in the thalamus are much lower than the concentrations necessary to occupy a major part of the GABAB receptors. It is unlikely that local accumulations of GHB reach concentrations 30-70-fold higher than the average brain levels. After injection of 3.5 mmol/kg GBL, a dose sufficient to induce SWD, brain concentrations reach 240 +/- 31 nmol/g (Snead, 1991) and GHB could thus stimulate the GABAB receptor. Like the selective and potent GABAB receptor agonist R(-)-baclofen, GHB causes a dose-related decrease in cerebellar cGMP. This decrease and the increase in SWD caused by R(-)-baclofen were completely blocked by the selective and potent GABAB receptor antagonist CGP 35348, whereas only the increase in the duration of SWD induced by GHB was totally antagonized by CGP 35348. The decrease in cerebellar cGMP levels elicited by GHB was only partially antagonized by CGP 35348. These findings suggest that all effects of R(-)-baclofen are mediated by the GABAB receptor, whereas only the induction of SWD by GHB is dependent on GABAB receptor mediation, the decrease in cGMP being only partially so. Taken together with the observations of Marescaux et al. (1992), these results indicate that GABAB receptors are of primary importance in experimental absence epilepsy and that GABAB receptor antagonists may represent a new class of anti-absence drugs.

4-Butyrolactone↗
PubMed1992

GABAB receptor antagonists: potential new anti-absence drugs.

The availability of new antagonists of the GABAB receptor which readily cross the blood-brain barrier has made it possible to investigate the role of GABAB-receptor-mediated transmission in the control of spike-and-wave discharges (SWD) in a strain of rats (GAERS) with genetic absence epilepsy. Systemic administration of R-Baclofen, a GABAB agonist, increased the duration of SWD, or elicited SWD-like oscillations in the cortical EEG of non-epileptic control rats. Conversely, administration of CGP 35348, a GABAB antagonist, either i.p. or p.o., dose-dependently suppressed the spontaneous SWD, as well as the SWD aggravated by concomitant injection of various GABAmimetic drugs, GHB, or anti-convulsants known to exacerbate absence seizures. These results demonstrate the involvement of GABAB-mediated neurotransmission in the development of SWD in generalized non-convulsive epilepsy. GABAB antagonists may thus be considered to be potentially specific anti-absence drugs.

Action Potentials↗
PubMed1992

Genetic absence epilepsy in rats from Strasbourg--a review.

We have selected a strain of rats and designated it the Genetic Absence Epilepsy Rat from Strasbourg (GAERS). In this strain, 100% of the animals present recurrent generalized non-convulsive seizures characterized by bilateral and synchronous spike-and-wave discharges accompanied with behavioural arrest, staring and sometimes twitching of the vibrissae. Spontaneous SWD (7-11 cps, 300-1,000 microV, 0.5-75 sec) start and end abruptly on a normal background EEG. They usually occur at a mean frequency of 1.5 per min when the animals are in a state of quiet wakefulness. Drugs effective against absence seizures in humans (ethosuccimide, trimethadione, valproate, benzodiazepines) suppress the SWD dose-dependently, whereas drugs specific for convulsive or focal seizures (carbamazepine, phenytoin) are ineffective. SWD are increased by epileptogenic drugs inducing petit mal-like seizures, such as pentylenetetrazol, gamma-hydroxybutyrate, THIP and penicillin. Depth EEG recordings and lesion experiments show that SWD in GAERs depend on cortical and thalamic structures with a possible rhythmic triggering by the lateral thalamus. Most neurotransmitters are involved in the control of SWD (dopamine, noradrenaline, NMDA, acetylcholine), but GABA and gamma-hydroxybutyrate (GHB) seem to play a critical role. SWD are genetically determined with an autosomal dominant inheritance. The variable expression of SWD in offsprings from GAERS x control reciprocal crosses may be due to the existence of multiple genes. Neurophysiological, behavioural, pharmacological and genetic studies demonstrate that spontaneous SWD in GAERS fulfill all the requirements for an experimental model of absence epilepsy. As the mechanisms underlying absence epilepsy in humans are still unknown, the analysis of the genetic thalamocortical dysfunction in GAERS may be fruitful in investigations of the pathogenesis of generalized non-convulsive seizures.

Action Potentials↗
PubMed1992

Cortical and thalamic lesions in rats with genetic absence epilepsy.

In generalized, non-convulsive, absence epilepsy, spike-and-wave discharges (SWD) are recorded in both the cortex and the thalamus. The effect of various cortical and thalamic lesions on the occurrence of spontaneous SWD was examined in rats from a strain with genetic absence epilepsy. Cortical ablations suppressed SWD recorded in the thalamus. KCl induced unilateral cortical spreading depression and transiently suppressed SWD in the ipsilateral cortex and thalamus; SWD recovered simultaneously in both structures. Bilateral thalamic lesions of the anterior nuclei, the ventromedial nuclei, the posterior area, or lesion of the midline nuclei did not suppress cortical SWD. However, large lesions of the lateral thalamus, including the specific relay and reticular nuclei, definitely suppressed ipsilateral SWD, and pentylenetetrazol, THIP or gammabutyrolactone failed to restore the cortical SWD. These results demonstrate that the neocortex and the specific thalamic nuclei are both necessarily involved in the generation of SWD in absence epilepsy.

Action Potentials↗
PubMed1992

Role of the thalamic reticular nucleus in the generation of rhythmic thalamo-cortical activities subserving spike and waves.

The role of the reticular thalamic nucleus (RTN) in pacing rhythmic cortical activities subserving spike-waves (SW) discharges has been investigated in rats. Intracellular recordings from thalamic slices in vitro demonstrated that RTN neurons from control animals possess a set of Ca2+/K+ membrane conductances which enable them to produce rhythmic oscillatory activities. In vivo, studies of Ca(2+)-conductance blockade by intrathalamic injections of Cd2+ were performed on 24 callosotomized Wistar rats displaying spontaneous SW discharges, bred at the Centre de Neurochimie, Strasbourg. A significant decrement in ipsilateral SW activity was consistently observed in all RTN-injected animals 40 min after Cd2+ injection. By contrast, animals which received Cd2+ injection into the ventroposterior complex (VP) showed only small changes in ipsilateral SW. It is concluded that Ca(2+)-dependent oscillatory properties of the RTN are critical for the expression of genetically determined SW discharges in the Wistar model.

Action Potentials↗
PubMed1992

Responses to N-methyl-D-aspartate are enhanced in rats with petit mal-like seizures.

The responses to the glutamate agonist N-methyl-D-aspartate (NMDA) were studied in the sensori-motor cortex of rats with petit mal-like seizures. In a first study, the changes in extracellular concentration of calcium elicited through ionophoretic application of NMDA at various depths in the cortex were measured in vivo. The results show that in the cortex of epileptic rats the NMDA responses are much more widely distributed than in the cortex of control rats. In a second study, a current-source density analysis of the responses elicited through electrical stimulation of the white matter was performed in slices of neocortex in vitro. These findings show that the NMDA-dependent component of the synaptic responses are more widely distributed and of longer duration in the cortex of epileptic rats than in that of control rats. Taken together, these results suggest that in this model of absence epilepsy NMDA-dependent mechanisms are important in the triggering and maintenance of epileptic activity.

Amino Acids↗
PubMed1992

Opposite effects of pentylenetetrazol on self-defensive and submissive postures in the rat.

In a previous work, using the resident-intruder situation, we have shown that a benzodiazepine inverse agonist could exert a "fear-promoting" effect, in decreasing self-defensive behaviours while increasing submissive postures. To further test this hypothesis, the effects of pentylenetetrazol on different forms of defensive behaviour were examined in male intruder rats confronted with offensive residents. Administration of pentylenetetrazol (10 and 20 mg/kg, IP) increased submissive postures such as immobility and on-the-back, but reduced self-defensive postures. Other active behaviours were not reduced, thus excluding a non-specific behavioural suppression. These results suggest that self-defensive and submissive behaviours can be dissociated and that anxiogenic compounds are more likely to increase submissive behaviours than self-defensive ones.

Aggression↗
PubMed1992

Involvement of intrathalamic GABAB neurotransmission in the control of absence seizures in the rat.

The role of intrathalamic GABAB neurotransmission in the control of absence seizures was investigated. In rats with genetic absence epilepsy, bilateral injections of R-baclofen (50, 100 and 200 ng/side), a selective GABAB receptor agonist, into the specific relay nuclei and the reticular nuclei of the thalamus increased spontaneous spike and wave discharges in a dose-dependent fashion, whereas injections of a GABAB antagonist CGP 35,348 (1, 2.5 and 5 micrograms/side) into the same sites decreased these seizures dose-dependently. The effect of R-baclofen (200 ng/side) on spike and wave discharges could be blocked by a subsequent injection of CGP 35,348 (1 microgram/side) at the same site. Injections of R-baclofen (200 ng) or CGP 35,348 (5 micrograms) into the midline thalamus had no effect on these seizures. In non-epileptic rats, bilateral injections of R-baclofen (1 microgram/side) into the specific relay nuclei induced synchronized rhythmic oscillations on the cortical electroencephalogram. The results suggest that GABAB receptors in the ventrolateral thalamus and in the reticular nuclei are involved in an oscillatory activity which underlies the rhythmic spike and wave discharges recorded during spontaneous generalized non-convulsive seizures.

Animals↗
PubMed1992

Positive transfer of audiogenic kindling to electrical hippocampal kindling in rats.

Audiogenic seizures in genetically susceptible rodents are provoked by intense acoustic stimulations which result in a tonic seizure associated with a short flattening of the EEG. These seizures have been shown to involve primarily brainstem structures. Daily exposure to sound for 30-40 days produced a permanent change in the evoked seizure with development of facial myoclonias, rearing and falling, or of tonic-clonic seizures accompanied by high amplitude cortical spike-and-wave discharges. Kindled audiogenic seizures appear similar to seizures kindled from amygdala or hippocampus, suggesting that repeated auditory stimulations cause a progressive propagation of the epileptic discharge toward limbic structures. To verify this hypothesis, the behavioral and EEG development of electrical hippocampal kindling has been studied in 7 non epileptic controls (NE), 8 acoustic susceptible (AS), and 8 audiogenic kindled rats (KAS). The behavioral and EEG development of the electrical hippocampal kindling was similar in the AS and the NE rats. However, 2 animals in the AS group but no controls exhibited behavioral running and bouncing during the course of hippocampal kindling. In the KAS group, the hippocampal kindling was clearly facilitated as compared to NE and AS: behavioral stage greater than or equal to 5 was reached in a mean of 4 stimulations in KAS versus 30 and 22 stimulations respectively in NE and AS groups. This positive transfer phenomenon suggests that during kindling of audiogenic seizures, epileptic discharge spreads from the brainstem to the forebrain and progressively involves the hippocampus.

Acoustic Stimulation↗