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S Brailowsky

Publications and source records attributed to S Brailowsky.

At least 19 recordsLinked to original sources
PubMed2000

Neocortical hyperexcitability after GABA withdrawal in vitro.

The sharp interruption of the intracortical instillation of exogenous gamma-aminobutyric acid (GABA), generates an epileptic focus in mammals. Seizures elicited by GABA withdrawal last several days or weeks. The present work reports that GABA withdrawal-induced hyperexcitability can be produced in vitro: a sudden withdrawal of GABA (5 mM; 120 min) or benzodiazepine (60 microM flunitrazepam) from the superfusion, induced a gradual increase in the amplitude of the evoked population spike (PS) recorded on neocortical slices. PS enhancement reached 150% above the control value 2.5 h after GABA withdrawal. GABA withdrawal-induced hyperexcitability was facilitated by progesterone. PS enhancement induced by GABA withdrawal was associated with an impairment of GABA transmission occurring before epileptiform discharges were fully established. Paired pulse inhibition and evoked [3H]-GABA release appear decreased; suggesting that cortical hyperexcitability as a result of GABA withdrawal involves pre-synaptic changes. Specific muscimol binding decreased during GABA superfusion but recovered after GABA withdrawal. However, the sensitivity of the post-synaptic response to 3alpha-OH-5alpha-pregnan-20-one or allopregnanolone (alloP) was enhanced after GABA withdrawal, suggesting a functional change in the GABA(A) receptors. The changes described may be the cellular correlates of the withdrawal syndromes appearing after interruption of the administration of GABA(A) receptor agonists.

Animals↗
PubMed2000

Long-lasting effects of GABA infusion into the cerebral cortex of the rat.

In electrophysiological terms, experimental models of durable information storage in the brain include long-term potentiation (LTP), long-term depression, and kindling. Protein synthesis correlates with these enduring processes. We propose a fourth example of long-lasting information storage in the brain, which we call the GABA-withdrawal syndrome (GWS). In rats, withdrawal of a chronic intracortical infusion of GABA, a ubiquitous inhibitory neurotransmitter, induced epileptogenesis at the infusion site. This overt GWS lasted for days. Anisomycin, a protein synthesis inhibitor, prevented the appearance of GWS in vivo. Hippocampal and neocortical slices showed a similar post-GABA hyperexcitability in vitro and an enhanced susceptibility to LTP induction. One to four months after the epileptic behavior disappeared, systemic administration of a subconvulsant dose of pentylenetetrazol produced the reappearance of paroxysmal activity. The long-lasting effects of tonic GABAA receptor stimulation may be involved in long-term information storage processes at the cortical level, whereas the cessation of GABAA receptor stimulation may be involved in chronic pathological conditions, such as epilepsy. Furthermore, we propose that GWS may represent a common key factor in the addiction to GABAergic agents (for example, barbiturates, benzodiazepines, and ethanol). GWS represents a novel form of neurono-glial plasticity. The mechanisms of this phenomenon remain to be understood.

Animals↗
PubMed1999

Susceptibility to focal and generalized seizures in Wistar rats with genetic absence-like epilepsy.

The susceptibility to develop cortically induced focal and generalized seizures was examined in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), an inbred strain of Wistar rats with absence epilepsy. A GABA-withdrawal syndrome induced after suppression of a 2-h intracortical GABA infusion was used as a model of focal epileptogenesis: localized cortical discharges appear at the infusion site within 1 h. GAERS were more prone to develop a GABA-withdrawal syndrome than non-epileptic inbred controls and non-selected Wistar rats. After a transient suppression of absence seizures following GABA infusion in GAERS, generalized spike-and-wave discharges and focal spikes were recorded simultaneously in the cortex. GAERS also showed a higher incidence of systemic pentylenetetrazol-induced convulsions at the dose of 25 mg/kg. Higher doses had similar convulsant effects in all groups. In conclusion, the results confirm a genetic susceptibility in GAERS and/or resistance in inbred non-epileptic rats to focal and generalized seizures involving the cortex. Rats with absence epilepsy appear to be more prone to seizures elicited by cortical GABA deficiency.

Animals↗
PubMed1999

Functional recovery from cortical hemiplegia in the rat: effects of a callosotomy.

The present work aimed at studying the participation of the homologous contralateral zone to a unilateral somatomotor cortex lesion, once the animals had showed a significant functional recovery. We studied recovery of coordinated walking after unilateral motor cortex aspiration in rats. A callosotomy was performed 20 days after the initial lesion, without significant effects. We conclude that after this time period, the intact hemisphere plays no role in the recovery process, suggesting that at this time point recovery does not depend on the integrity of corpus callosal fibers at this rostral-caudal level.

Animals↗
PubMed1998

Alterations in GABAA receptor alpha 1 and alpha 4 subunit mRNA levels in thalamic relay nuclei following absence-like seizures in rats.

Modification of GABAA receptor mRNA levels by seizure activity can regulate general neuronal excitability. The possibility of absence seizure-induced alteration in GABAA receptor alpha 1, alpha 4, beta 2, and gamma 2 subunit gene expression in thalamic relay nuclei was studied in a rat model of absence seizures induced by gamma-hydroxybutyric acid (GHB). We observed a marked increase in alpha 1 mRNA and a corresponding decrease in alpha 4 mRNA in thalamic relay nuclei 2-4 h after the onset of GHB-induced absence seizures (when the seizures were terminating). These changes were selective to these alpha isoforms as neither beta 2 nor gamma 2 mRNA changed following seizures and occurred only in thalamic relay nuclei but not in hippocampus, a structure from which absence seizures do not evolve. The alterations in alpha 1 and alpha 4 mRNA persisted until about 12 h, and by 24 h after the seizure-onset the mRNA levels normalized. Blocking GHB-seizures produced no change in the levels of alpha 1 and alpha 4 mRNA in thalamic relay nuclei, suggesting that seizures themselves were responsible for mRNA alterations. In order to determine if absence seizure-induced changes in alpha 1 and alpha 4 mRNA had any physiological significance, GHB was readministered in rats 6 and 24 h after the onset of seizures. The total duration of GHB-seizures was found to be significantly decreased when GHB was readministered at 6 h but not 24 h after the seizure-onset. These results suggest that absence seizures regulate GABAA receptor alpha 1 and alpha 4 gene expression in thalamic relay nuclei as a compensatory mechanism by which absence seizures are terminated.

4-Butyrolactone↗
PubMed1998

Absence seizures decrease steroid modulation of t-[35S]butylbicyclophosphorothionate binding in thalamic relay nuclei.

Interaction of gamma-aminobutyric acid (GABA), pentobarbital and two neuroactive steroids on t-butylbicyclophosphorothionate ([35S]TBPS) binding to GABAA receptors in thalamus was studied during absence seizures. In control brain sections, the steroids alphaxalone and tetrahydrodeoxycorticosterone (at low 0.1-1 microM concentrations) increased [35S]TBPS binding in thalamic relay nuclei. Both GABA and pentobarbital dose-dependently decreased [35S]TBPS binding in these nuclei. A significant decrease in the ability of steroids to increase [35S]TBPS binding in thalamic relay nuclei was observed during absence seizures induced by gamma-hydroxybutyric acid (GHB). This loss of steroid effect on binding was 1) selective to steroids only as GABA and pentobarbital modulation of [35S]TBPS binding in these nuclei did not change significantly and 2) not causally related to the generation of GHB-induced absence seizures as it was not observed at the onset of GHB-seizures but developed 30 min after the seizure-onset. We tested whether absence seizures were critical for the development of this loss of steroid effect on [35S]TBPS binding in thalamic relay nuclei. The ability of the steroids to increase [35S]TBPS binding in relay nuclei was preserved when GHB-seizures were blocked. When the duration of GHB-seizures was prolonged, the loss of steroid effect on [35S]TBPS binding in thalamus persisted throughout the seizure-duration. These findings suggest that absence seizures cause a rapid loss of steroid effect on [35S]TBPS binding to GABAA receptors in thalamic relay nuclei.

Action Potentials↗
PubMed1995

Effects of GABAB receptor antagonists on two models of focal epileptogenesis.

The acute effects of two GABAB receptor antagonists (phaclofen and CGP-35348) were studied in two types of epileptogenic activity: that produced by intracortical injections of baclofen and that appearing after withdrawal of chronic intracerebral GABA infusion (the GABA-withdrawal syndrome, GWS). Intracortical baclofen induced two types of electrographic paroxysmal discharges: one consisting of single spike-and-wave (pattern I) and another of polyspike-and-wave patterns (pattern II). Both patterns showed similar latencies and temporal evolution of spike frequency discharges. Phaclofen, applied directly into the baclofen-induced epileptogenic focus, suppressed pattern II but was ineffective in modifying both pattern I and the GWS. CGP-35348, administered systemically, inhibited both patterns I and II. Intracortical microinjection of baclofen or phaclofen in rats showing a GWS had no effect, nor the systematically given CGP 35348. These results indicate a differential participation of GABAB receptors in GABA-related epileptic syndromes of cortical origin.

Animals↗
PubMed1995

Allopregnanolone potentiates a GABA-withdrawal syndrome in the rat cerebral cortex.

We have studied the neuromodulatory effect of the neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone-3 alpha-5 alpha P-) in the GABA-withdrawal syndrome (GWS). This is a model of partial epilepsy consisting of an enduring paraoxysmal activity recorded at the site of GABA infusion that depends, for its induction, on GABA receptor activation. Rats were chronically implanted for frontal and occipital EEG recording with infusion cannulae fixed on the somatomotor cortical region. When the neurosteroid was infused after or concurrently with GABA, a potentiation of the GWS (i.e. shorter latency and prolonged duration) was observed. No modifications in EEG activity were detected when allopregnanolone was administered alone or prior to GABA administration. These results indicate a neuromodulatory effect of allopregnanolone, dependent on the presence of GABA at the receptor site.

Animals↗
PubMed1994

Decrease of glutamate decarboxylase activity after in vivo cortical infusion of gamma-aminobutyric acid.

gamma-Aminobutyric acid (GABA) levels and the activity of glutamate decarboxylase were measured in homogenates of rat brain cortical tissue, at different times after chronic intracortical infusion of GABA in vivo during 2, 6 or 24 h. Cortical electrical activity was also recorded. As previously described, about 1 h after cessation of the infusion epileptic discharges were observed (GABA-withdrawal syndrome), which lasted for several days. At zero time after cessation of the infusion, before the appearance of seizures, GABA levels were increased 3-6-fold and glutamate decarboxylase activity was decreased 27-48% in the infused cortex, as compared to the contralateral cortex or to tissue from control intact rats. During epileptic discharges GABA levels gradually returned to normal values. In contrast, glutamate decarboxylase activity remained decreased during seizures and returned to normal only after recovery from the GABA-withdrawal syndrome. These results suggest that the persistent decrease in the activity of the decarboxylase is due probably to a lowered amount of the enzymatic protein, occurring as a consequence of a temporarily elevated intracellular GABA concentration. The decreased rate of GABA synthesis might be involved in the pathophysiology of the GABA-withdrawal syndrome.

Amino Acids↗
PubMed1993

Chronic infusions of GABA into the medial prefrontal cortex induce spatial alternation deficits in aged rats.

It has been proposed that functions associated with the prefrontal cortex could change as a consequence of aging. Previous experiments in young rats have demonstrated that anatomical lesions or chronic GABA infusions into this area produce deficits in spatial delayed alternation tasks. The present study examines the effect of chronic (7 days) GABA or saline infusion into the prefrontal cortex on the performance of delayed alternation task in old rats (24 months). The results suggested that aged rats needed more sessions to acquire the delayed alternation task. GABA infusions into the prefrontal cortex produced deficits in spatial alternation tasks similar to those previously observed in young rats. Performance rapidly recovered after the infusion period. Histological analysis showed similar lesion size in both groups. The results suggest that aged prefrontal cortex and/or related areas participating in the acquisition of the delayed alternation task are more sensitive to aging processes. Furthermore, the prefrontal cortex is important for the retention of a previously learned spatial delayed alternation task. The structures involved in functional recovery from these deficits appear to be fully functional in aged rats.

Aging↗
PubMed1992

Hyperexcitability of hippocampal CA1 region in brain slices after GABA withdrawal.

The interruption of GABA infusion in the cerebral cortex and in the hippocampus produces electrographic seizures in rats. Here, we have used the hippocampal slice preparation to induce a 'GABA withdrawal syndrome (GWS)'. With the stimulation parameters used (0.2 Hz, 200 microseconds), activation of the Schaffer afferents produced one population spike in the CA1 subfield, while multiple population spikes were observed in the slices previously incubated in GABA. Also, we recorded an increase in the amplitude of the population spike when compared to its control value. Paired pulse test showed absence of recurrent inhibition in these slices. These results suggest a dysfunction in GABAergic neurotransmission.

Animals↗
PubMed1992

Chronic infusion of GABA into the nucleus basalis magnocellularis or frontal cortex of rats: a behavioral and histological study.

In order to determine the influence of the nucleus basalis magnocellularis (NBM) on the sensorimotor function of the frontal cortex (FCx) of the rat, GABA at various concentrations (10, 50 or 100 micrograms.microliters-1) was administered into these structures. GABA was infused for four consecutive days after which saline was infused for another four. On the contralateral side the order of administration was reversed. Each structure received GABA while its homologous on the contralateral side received saline. Before, during and after drug infusion, the animals were weighted and their performance in two non-reinforced behavioral tasks (beam walking and spontaneous rotation) was examined. When GABA was infused into the FCx, a dose-dependent and reversible sensorimotor deficit was observed along with a behavioral withdrawal syndrome upon GABA discontinuation. When GABA was administered into the NBM, a reversible sensorimotor deficit was observed only when GABA was infused at the highest concentration. In this case no behavioral changes were observed upon GABA discontinuation. Histologically, a gliosis was observed in the NBM in which GABA was infused at the two highest concentrations without saline pretreatment; these effects were not observed when GABA was infused without saline pretreatment into the FCx. In relation to our previous findings, these results suggest that i) the FCx is directly involved in the expression of sensorimotor functions, while the influence of the NBM on these functions appears only after severe subcortical damage, ii) a GABA withdrawal syndrome is observed following GABA administration in the FCx but not in the NBM, and iii) "tonic" effects of GABA are dose-related and partially dependent upon pretreatment conditions and the brain region infused.

Analysis of Variance↗
PubMed1992

Effects of 3-hydroxy,3-ethyl,3-phenylpropionamide (HEPP) on rat models of generalized and focal epilepsy.

The GABA withdrawal syndrome (GWS) is a new model of focal epilepsy in which paroxysmal activity is induced through the interruption of a chronic, intracortical infusion of GABA. Preliminary studies have shown extraordinary resistance of this epileptogenic activity to classic anticonvulsants including diazepam, the most effective agent for treating status epilepticus. However, GWS can be inhibited by GABA itself. The rat with petit mal-like seizures is a genetic model of generalized non-convulsive epilepsy (GNCE), with behavioral characteristics and electrical (spike-and-wave discharges) signs resembling absences. Moreover, GABAmimetics aggravate this type of seizure. Rats with GWS induced by cessation of a localized GABA infusion (50 micrograms/microliters/h for 24 h), and the rat model of GNCE, were treated with HEPP, a new anticonvulsant agent. In the case of GWS, the drug produced a significant decrease of focal spike activity in animals which started discharging at low frequencies while in rats with higher frequency discharge, HEPP was without effect. HEPP administered on the second day of the GWS in naive rats had no effect. In rats with GNCE, doses of 50 and 100 mg/kg i.p. blocked the spike-and-wave discharges. The higher dose produced sedation in this absence seizures model. Although the mechanism of action of HEPP is still unknown, its unique antiepileptic profile deserves further studies.

Animals↗
PubMed1991

Metabolic anatomy of the focal epilepsy produced by cessation of chronic intracortical GABA infusion in the rat.

Cessation of chronic (5 days), unilateral infusion of GABA into the somatomotor cortex of rats induces focal epileptic spikes which remain limited to the infused site and never evolve into generalized seizures. We have considered this finding as a new model of focal epilepsy and named it "GABA withdrawal syndrome". In the present study, we have measured local cerebral glucose utilization in order to map the cortical and subcortical regions involved in the GABA withdrawal syndrome. Local cerebral glucose utilization increased two- to three-fold in a 1-1.5 mm diameter area, involving all the cortical layers at the GABA-infusion site. This hypermetabolic area contained a central (1-2 mm diameter) hypometabolic zone showing neuronal depopulation in some animals. Except for the epileptic focus, the hemisphere ipsilateral to the infusion site was slightly hypometabolic. However, there was a large increase (three- to five-fold) in some ipsilateral thalamic nuclei (posterior oralis, ventralis postero-lateralis, centralis lateralis, ventralis lateralis and reticularis thalami nucleus). The local cerebral glucose utilization of the contralateral cortex and thalamus were unchanged. The present results confirm the focal nature of the epileptogenic syndrome produced by stopping chronic, intracortical GABA infusion. These results are markedly different from those described in the penicillin focal epilepsy model. Our data also show that specific ipsilateral thalamic relays may, by an as yet unknown mechanism, play a role in maintaining paroxysmal activity during the GABA withdrawal syndrome.

Animals↗