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Biomedical subjects

S Brailowsky

Publications and source records attributed to S Brailowsky.

At least 37 records · Page 2Linked to original sources

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↗

Chronic infusions of GABA into the medial frontal cortex of the rat induce a reversible delayed spatial alternation deficit.

The effects of bilateral infusions of GABA into the medial frontal cortex of the rat were studied in a delayed spatial alternation task. It was found that GABA (500 mM, 1 microliter/h during 7 days) impaired the performance of the rats in the previously learned task. Upon interruption of the treatment, the animals rapidly recovered normal performance scores. The results show that GABA infusions produce functional deficits similar to those produced by lesions of the frontal cortex. Moreover, the deficits are reversible upon interruption of the treatment. This technique may therefore be a useful tool for studying frontal lobe functions and the involvement of GABAergic mechanisms in cognitive processes.

Animals↗

Chronic infusion of GABA and saline into the nucleus basalis magnocellularis of rats: II. Cognitive impairments.

In order to assess sensorimotor and/or cognitive modifications following chronic inhibition of nucleus basalis magnocellularis (NBM) neurons, rats trained in two radial maze paradigms (the classical version of the test and a modified version introducing a one-hour delay between the fourth and the fifth choice) received chronic infusion of gamma-aminobutyric acid (GABA) into the NBM area. GABA (10 and 50 micrograms/microliters/h) was infused for 3 days into the NBM contralateral to their preferred turning direction in the radial maze. Simultaneously, saline (NaCl 0.9%; 1 microliter/h) was infused into the contralateral NBM. GABA and saline infusions were alternated for the subsequent 3-day period. One week later, we investigated the rats' ability to learn a multiple trial passive avoidance task. At the dose of 50 micrograms/microliters, GABA infusion produced (1) a turning bias ipsilateral to the side first infused with GABA, (2) transitory cognitive impairments in radial maze tasks and (3) a deficit in the acquisition of the passive avoidance task. At the dose of 10 micrograms/microliters, the same behavioral deficits were observed except that (1) the turning bias was reversed by the contralateral GABA infusion and (2) cognitive impairments in the radial maze were observed only when a delay was inserted between the fourth and the fifth choice. Histologically, we found a dose-dependent gliosis in the NBM area first infused with GABA. These data suggest a reactivity of the NBM to GABAergic manipulations and the intervention of this structure in both sensorimotor and cognitive processes involved in the radial maze paradigms.

Acetylcholine↗

Relationship between tolerance to GABAA agonist and bursting properties in neocortical neurons during GABA-withdrawal syndrome.

The interruption of intracortical, chronic GABA infusion is known to give rise to 'GABA withdrawal syndrome' (GWS) consisting of electroencephalographic paroxysmal focal activities, associated with behavioral epileptic signs. Neocortical slices were obtained from rats presenting the GWS (GWS slices), and intracellular recordings were performed in the vicinity of the gamma-aminobutyric acid (GABA)-infused site. Electrical stimulation of the underlying white matter induced paroxysmal depolarization shifts (PDSs) in virtually all neurons. Bath-applied GABA (1-10 microM) had no effect on these neurons, while the same dose range was found effective in blocking action potentials in saline-infused cortex slices obtained from control rats. In the GWS slices a population of neurons presented, in addition to synaptically induced PDSs, voltage-dependent and cobalt-sensitive PDSs and bursts of action potentials induced by depolarizing current injections. These intrinsic bursting neurons were unresponsive to high doses of GABA (100 microM). Dose-response curves of isoguvacine, a specific GABAA agonist, showed a shift to the right for the intrinsic bursting cells whatever the parameter measured (depolarization or conductance increase): the ED50 was 50-100 times higher for intrinsic bursting cells than for other non-intrinsic bursting cells, thus indicating that intrinsic bursting cells are tolerant to GABAA agonist. This tolerance may result from a decreased number of receptors or from a change in their properties as a consequence of the previous prolonged GABA infusion. The decrease in the GABA efficacy could lead to disinhibition and could thus give the appearance of epileptic events.

Animals↗

Effects of localized, chronic GABA infusions into different cortical areas of the photosensitive baboon, Papio papio.

The effects of chronic (7 days) intracortical GABA infusions were investigated in both naturally photosensitive and non-photosensitive baboons. Bilateral and unilateral infusions into motor and occipital regions blocked photosensitivity, while premotor and prefrontal cortex infusions had no effect on the electro-clinical manifestations of this type of reflex epilepsy; the monkeys with prefrontal GABA infusions, however, showed selective attention deficits, detected with the delayed response test. In all cases a GABA withdrawal syndrome, appearing as epileptogenic spontaneous activity localized to the infused sites, was found at the cessation of GABA application. We conclude that GABAergic systems localized at discrete cortical areas play an important role in photosensitivity and in the modulation of cognitive processes in the monkey.

Animals↗

The GABA-withdrawal syndrome: a new model of focal epileptogenesis.

A novel model of focal, cortical epilepsy is described. Chronic (6 h to 14 days), localized application of gamma-aminobutyric acid (GABA) into the somatomotor cortex of rats induces, upon withdrawal, the appearance of epileptogenic activity with maximal electrographic expression circumscribed to the infused site. This GABA-withdrawal syndrome (tested for a 100 micrograms/microliter/h dose) lasted from 24 to 168 h (mean values). A significant correlation was found between infusion time and duration of the excitability rebound, with the longer duration corresponding to the shorter infusion time. A distant lesion effect was observed in the thalamic area of cortical projection. The potential use of this neurotransmitter-induced phenomenon in the study of brain plasticity in general, and of epilepsy in particular, is discussed.

Animals↗

Local asymptomatic status epilepticus induced by withdrawal of GABA infusion into limbic structures.

Most of the experimental models of status epilepticus result either from administration of a variety of excitatory neurotoxins or repeated electrical stimulation. Here we propose a new model based on the withdrawal of chronic gamma-aminobutyric acid (GABA) infusion into limbic structures via osmotic minipumps. Appearing with a latency of about 50 min, continuous pseudo-rhythmic EEG epileptic spiking was elicited for about 12-24 h after removal of GABA infusion in hippocampus or amygdala. No apparent distant brain damage was observed. This model differs from many others by several features and could result from different mechanisms.

Amygdala↗

Anticonvulsant effects of localized chronic infusions of GABA in cortical and reticular structures of baboons.

We studied the effects of chronic (7 day) infusions of GABA (100 and 20 micrograms/microliter, 10 microliter/h) applied in different cerebral structures of baboons made photosensitive by a subconvulsant dose of allylglycine. The GABA infusion has partial anticonvulsant effects when applied to the motor cortex, reticular magnocellular nucleus (RMC), or substantia nigra (SN), but when directed to the prefrontal cortex (area 8) it has no effect. These anticonvulsant effects of GABA infusion are more important when GABA is infused into the motor cortex, where paroxysmal discharges (PDs) originate, than when it is infused into the RMC. In contrast, the anticonvulsant effects on light-induced generalized seizures are more pronounced when GABA is infused into the RMC than when it is infused into the motor cortex. GABA infusion into the SN has no effect on PDs and myoclonia and blocks seizures less effectively than the RMC infusion. These results are in accordance with the role of the motor cortex as a generator of PDs and of RMC in the generalization of seizures. Focal paroxysmal EEG and clinical activities, previously reported to appear at the end of the motor cortex GABA infusion, were not observed after RMC or SN infusions. However, behavioral hyperactivity occurring at the end of subcortical GABA infusions was observed. These behavioral signs could correspond to the clinical expression of a GABA withdrawal syndrome.

Animals↗

Unilateral infusion of GABA and saline into the nucleus basalis of rats: 1. Effects on motor function and brain morphology.

Motor behavior was investigated in rats following acute and chronic gamma-aminobutyric acid (GABA) microinfusions into the nucleus basalis. For acute treatment, the rats received GABA (100 micrograms in 1 microliter), then saline, or these solutions in the reverse order, into the nucleus basalis contralateral to their preferred turning direction in a radial maze. For chronic treatment, half the rats received saline (1 microliter/h for 4 days), and than GABA (100 micrograms/microliters/h) for the same period of time ('saline-first' group). In the other half, this sequence was reversed ('GABA-first' group). Acute microinjections of GABA decreased turning towards the non-injected side; chronic treatment enhanced this effect by reversing the preferred turning direction. Return to initial turning direction was observed after acute GABA-injection in both experimental groups, but only in the 'saline-first' group after chronic treatment. The 'GABA-first' group showed gliosis in and around the nucleus basalis area and a reduction of cortical acetyl-cholinesterase-positivity which were significantly greater than in the 'saline-first' group. This, chronic saline pretreatment is associated with diminished neurotoxicity of chronic GABA infusion and with a reversibility of the drug-induced behavioral effects.

Animals↗

Epileptogenic gamma-aminobutyric acid-withdrawal syndrome after chronic, intracortical infusion in baboons.

We studied the effects of chronic (7 days) infusion of GABA (100 micrograms/microliter) applied intracortically into the fronto-rolandic (FR) area of baboons, via osmotic minipumps. In photosensitive animals, bilateral GABA application produced a complete blockade of the paroxysmal discharges and associated clinical signs induced by intermittent light stimulation. Unilateral administration had similar effects, although these developed more gradually. At the end of the infusion period, both photosensitive and non-photosensitive animals showed a transitory state (3-4 days) of cortical hyperexcitability (spontaneous epileptogenic activity) localized to the infused area. The data indicate a role of GABA both in the natural photosensitivity of the epileptic baboon and in the withdrawal syndrome consecutive to the sudden interruption of chronically enhanced GABA levels in the FR territories of this monkey.

Animals↗

Anticonvulsant effect of intracortical, chronic infusion of GABA in kindled rats: focal seizures upon withdrawal.

The behavioral and electrographic effects of chronic (7 days), localized infusion of GABA (100 micrograms/microliter) into the somatomotor cortex of fully amygdala-kindled rats is reported. The animals were stimulated once daily until a stage 5 (generalized clonic seizure) was obtained for five consecutive days. After determination of a stable seizure triggering threshold, the rats were implanted with osmotic minipumps (1 microliter/h for 7 days) connected to previously implanted bilateral cannulae. Amygdala stimulation was continued for 14 successive days. GABA infusion reduced the motor seizure without significantly modifying the limbic afterdischarge. This effect lasted until termination of drug application, with recovery of stage 5 convulsions on the following 3 to 5 days. No effects were observed in saline-infused animals or in rats with unilateral GABA treatment. Upon cessation of GABA treatment (removal of the osmotic devices by day 7 postimplantation), spontaneous epileptic discharges localized to the infusion sites appeared. In some animals, the abnormal activity was accompanied by behavioral signs of myoclonus. This cortical hyperexcitability lasted 2 to 24 h, with complete recovery afterward. These data indicate that two types of focal epilepsy may coexist independently in the same animal and provide confirmation of previous observations in the monkey on the existence of a "GABA-withdrawal syndrome" after chronic, focal infusion of the amino acid.

Amygdala↗

Phenytoin increases the severity of cortical hemiplegia in rats.

The effects of systemic phenytoin administration on the motor deficit resulting from a cortical lesion were studied in rats trained to walk coordinately on a narrow beam. The somatomotor cortex lesion was produced by an indwelling cannula through which saline or GABA were infused chronically via an osmotic minipump. Phenytoin (50 mg/kg i.p.) administered between days 3 and 5 after the intracortical catheter implantation produced a significant increase in the severity of the resulting hemiplegic syndrome. This DPH effect was more noticeable in those animals also receiving intracortical GABA infusions. The anticonvulsant at the dose used had no effect on motor performance when administered preoperatively or when given to the animals 14 days after surgical intervention when their hemiplegic syndrome had cleared. These findings suggest that phenytoin administration to brain-damaged individuals in the initial postlesion stage may be deleterious.

Animals↗

gamma-Aminobutyric acid-induced potentiation of cortical hemiplegia.

A novel model of hemiplegia in young and aged rats is described. Osmotic minipumps were used to deliver a chronic (7 days), localized application of gamma-aminobutyric acid (GABA) (100 micrograms/microliter/h), to the somatomotor cortex of unrestrained rats. This resulted in an easily quantifiable, contralateral and reversible motor syndrome in both young and aged animals. In the young group, the motor deficit cleared over 5-day period, while in the aged animals it persisted for at least a 2-week period. Control animals treated with saline-filled minipumps did not develop a long-lasting motor deficit. The GABA-induced facilitation of hemiplegia due to small motor cortex lesions and the age effects on behavioral recovery of function are discussed. Cortical inhibitory mechanisms may play a role in debilitating syndromes such as stroke or post-epileptic paralysis.

Animals↗

Altered peripheral and brainstem auditory function in aged rats.

A technique for conducting free-field brainstem auditory evoked potential (BAEP) audiometry in unanesthetized, unrestrained rats revealed a non-recruiting 18 dB elevation of click threshold in aged rats. BAEPs were first recorded in young and aged rats to clicks of equal intensity (80 dB SPL). Compared to the young group, aged animals exhibited longer wave I and wave IV latencies with no difference seen in the I-IV central conduction time. The prominent negative wave (No) following wave IV was also delayed and the I-No and IV-No conduction times increased in the aged group. When BAEPs were recorded to clicks with intensities adjusted to 35 dB above individual threshold, no differences in wave I or wave IV latencies or in the I-IV central conduction time were found between groups. However, the No component was delayed and the I-No and IV-No conduction times remained prolonged in the aged group. The results suggest that in addition to changes in peripheral auditory structures, changes in the rostral auditory brainstem accompany age-related hearing loss in rats.

Aging↗

Surface auditory evoked potentials in the unrestrained rat: component definition.

Auditory evoked potentials (AEPs) to click and pure tone stimuli were recorded in unrestrained, unanesthetized rats. The middle latency rat AEPs (N17, P23, N38) had midline scalp distributions similar to human MAEPs and were recorded to within 15 dB above BAEP threshold. In contrast to human MAEPs, rat MAEPs were decreased in amplitude at high stimulation rates and only the N17 component was unaltered by slow wave sleep. The longer latency N50, N80 and P130 components had several response properties comparable to human N100-P200 vertex potentials. These included restricted midline fronto-central scalp distributions, progressive increases in amplitude at ISIs up to 4-8 sec and marked attenuation during slow wave sleep. The frequency sensitivity of the rat AEP revealed a decreased response to pure tones below 4 kHz but robust responses for stimuli up to at least 45 kHz. There was a notch in the rat audiogram with decremented component amplitudes to pure tone stimuli centered at 35 kHz. When equated for intensity, click and pure tone stimuli in the range of the rats maximal audiometric sensitivity (8-20 kHz) generated comparable AEP components. These results provide normative data on rat surface recorded AEPs. It is suggested that these surface recorded rat AEPs are generated by subcortical neural systems involved in the detection of auditory transients.

Animals↗

Inhibitory modulation of cat somatosensory cortex: a pharmacological study.

In anesthetized preparations, GABA and taurine produced rapid, reversible inhibition of the negative component (N20) of the primary somatosensory evoked potential (SEP) without effect on the earlier positivity (P11). This effect was also produced by low doses of 4-aminopyridine. Neither bicuculline or picrotoxin antagonized these drug effects. A predominance of type B GABA receptors in the superficial layers of the somatosensory cortex is proposed.

4-Aminopyridine↗

Morphine-theophylline interaction: antagonism or facilitation?

1 Morphine-theophylline interactions were investigated in both acute and narcotic-dependent preparations, in vitro and in vivo, using four different experimental models: LD50 doses of morphine and naloxone in the mouse; naloxone-induced contractions in the electrically-stimulated and opiate-dependent isolated ileum of the guinea-pig; naloxone-induced jumps in the mouse; an calcium uptake in synaptosomal preparations. 2 The LD50 of morphine was significantly increased by theophylline. 3 The lethal effect of theophylline was potentiated by pretreatment of the animals with naloxone. 4 Theophylline displayed protective effects in the inhibitory response to morphine and antagonism to the withdrawal response induced by naloxone in the electrically-stimulated isolated ileum of the guinea-pig. 5 The number of jumps induced by naloxone in morphine-dependent mice was significantly diminished by theophylline. 6 The inhibitory effect of morphine on the synaptosomal uptake of calcium was decreased by theophylline. 7 The effects of both morphine and theophylline on the cyclic nucleotides and the possible role of calcium in these actions are discussed.

Animals↗