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This study was designed to evaluate the predictive value of event-related potential (ERP; N2 and P3b) in patients with mild cognitive impairment (MCI). Seventy-one patients with MCI were selected and compared with 31 healthy control subjects. They benefited from an initial assessment that included a neuropsychological evaluation and ERP. We followed them up for 1 year, and during their last visit, they benefited again from ERP and neuropsychological tests. At the end of the study, 2 subgroups of patients with MCI were differentiated according to their clinical evolution from baseline to follow-up: 41 MCI progressors (MCI-P) and 30 MCI nonprogressors (MCI-non P). The MCI-P patients had a significant decline in their executive functions compared with the MCI-non-P group at baseline and follow-up especially on trail making test B (TMT B) and verbal fluency (P0.0001). At baseline, MCI-P had increased P3b latencies and low P3b amplitudes compared with MCI-non P. The MCI-P showed an inversion of the P3b rostrocaudal gradient with a significant decrease in the amplitude of P3b in the parietal area compared with the MCI-non P. At follow-up, 17 MCI-P patients had converted to Alzheimer's disease (AD). There was a significant rate of decline of the amplitude of N2 and P3b in the frontal area among the groups. Furthermore, the MCI-P had a higher decrease in the rostrocaudal gradient of P3b and prolonged N2 and P3b latencies than the MCI-non P did. The sensitivity and specificity were approximately 80% and 70%, using P3b amplitude to discriminate the MCI-P from the MCI-non P. Our study underlines the interest of using N2 and P3b as neurophysiological markers for measuring MCI decline progression.

Event-related potentials (ERPs) have a large application in the evaluation of cognitive processes, particularly in Alzheimer's disease (AD). The aim of the present study was to evaluate the clinical relevance of event-related evoked potentials (N2 and P3 subcomponents) in early diagnosis of AD and mild cognitive impairment (MCI). We prospectively studied 60 subjects. They all underwent the following investigations: neurologic and neuropsychological examination; functional evaluation, i.e., ERPs; cerebral imagery (morphologic and functional). Subjects were classified into 3 groups: group 1: 30 dementia of Alzheimer type (NINCDS-ADRDA, DSM-IV criteria); group 2: 20 MCI; and group 3: 10 control subjects. ERPs were significantly different between the groups (AD, MCI, control subjects), with a marked increase of P3 latencies, particularly when compared with N2 latencies (P < 0.0001). Furthermore, sensitivity was 87% to 95% for the differentiation of AD patients from MCI and control subjects, using prolonged P3 latencies (specificity, 90% to 95%), whereas using N2 prolonged latencies, sensitivity was 70% to 75% (specificity, 70% to 90%). Moreover, in the MCI group, N2 latencies strongly discriminated MCI from control subjects, with 90% sensitivity and 70% specificity and correctly categorized 80% of MCI subjects against 73% for P3. The abnormalities of N2 and P3 components may be linked, in AD and MCI, to an alteration of automatic and controlled attention processing.

Prolonged use of sedative drugs frequently leads to oversedation of intensive care patients. Clinical assessment scales are not reliable in deeply sedated patients. Parameters obtained from spectral and bispectral analysis of electroencephalogram (EEG) records have been combined to create an index (BIS) to monitor anesthesia depth. The role of such parameters in monitoring the depth of the sedation in intensive care unit (ICU) patients has yet to be determined. We designed the present prospective study to redefine and calculate available spectral and bispectral parameters from raw EEG records and estimate their clinical relevance for the diagnosis of under- or oversedation levels in ICU patients. Forty adult patients receiving continuous midazolam and morphine sedation were included. We obtained 167 clinical evaluations of sedation level using Ramsay and COMFORT scales along with an EEG record of 300 s. Six spectral parameters-relative power of 4 frequency bands (beta, alpha, Theta, and delta), 95th percentile of the power spectrum (SEF95), and 50th percentile of the power spectrum (SEF50) and four bispectral parameters, real triple product, bispectrum (Bispectrum), bicoherence, and ratio 10-were calculated. The relevance of each of these parameters and combinations in predicting too light (Ramsay 1 and 2) or deep (Ramsay 5 and 6) sedation levels was assessed. These calculations were performed before and after exclusion of the agitated patients, whose COMFORT 4 score was above 2. The most relevant parameters for predicting levels of deep sedation (Ramsay 5 and 6) were ratio 10 (area under the curve = 0.763; 95% confidence interval, 0.679-0.833) and SEF95 (area under the curve = 0.687; 95% confidence interval, 0.597-0.767). The most relevant parameters for predicting light levels of sedation (Ramsay 1 and 2) were also ratio 10 (area under the curve = 0.829; 95% confidence interval, 0.695-0.917) and SEF95 (area under the curve = 0.798; 95% confidence interval, 0.650-0.898). There is a modest improvement in relevance of their linear combination in predicting sedation level. Results were similar after exclusion of agitated patients. We conclude that various calculated EEG descriptive parameters exhibited large interindividual variability. There was a strong correlation between EEG spectral and bispectral parameters. Bispectral analysis slightly improves the predictive power of simple spectral analysis in distinguishing too light or deep sedation levels in ICU patients.Spectral edge frequency 95 and Ratio 10 are the most relevant electroencephalogram (EEG) indexes for monitoring the level of sedation in intensive care unit patients but calculated EEG values exhibited large interindividual variability. Bispectral analysis of EEG provides a slight improvement over simple spectral analysis.

Seven days after in vivo intrahippocampal administration of NMDA, 3'-OH DNA fragmentations and Bax protein expression were detected in hippocampal neurons of p53+/+ but not p53-/- transgenic mice. Interestingly, neurons showing pycnosis, an early apoptotic phenomena, were present in all genotypes. These results confirm that apoptotic 3'OH DNA fragmentations and Bax protein induction during NMDA-induced apoptosis in adult hippocampal neurons are p53 dependent.

The time course of induction of the proto-oncogene c-fos and the inducible heat shock hsp70 gene was studied from 5 minutes to 24 hours at both transcriptional (c-fos and hsp70 mRNA) and translational levels (C-FOS and HSP72 proteins) in the rat hippocampus and piriform cortex (Pir) after soman-induced seizures. Induction of c-fos was noticed as early as 5 minutes after seizures onset in all fields of hippocampal formation (CA1, CA3, CA4, and dentate gyrus) and in piriform cortex. The most intense induction was observed in piriform cortex. A sustained activation of c-fos occurred in Pir and in CA1, CA3, and CA4 areas of hippocampus. Nevertheless, histological analysis showed rare affected neurons in CA4, whereas damage was severe in Pir and in CA1 and CA3 hippocampal subfields. Induction of hsp70 mRNA occurred but was delayed in all areas previously exhibiting c-fos expression. Nevertheless HSP72 protein was never expressed in the structures where injury was high (i.e., CA1 and piriform cortex) and mainly occurred in the less damaged structure (i.e., CA4 area of hippocampus). Regional expression of glial fibrillary acidic protein mRNA was also studied in order to exclude an astroglial origin of the c-fos and hsp70 gene inductions. Our results demonstrated that after soman induced-seizures 1) there was no strict correlation between time course or intensity of neuronal c-fos induction and subsequent neuropathology, and 2) the most lesioned areas did not express HSP72 protein in spite of intense mRNA induction, suggesting that transcriptional and translational events for hsp70 gene might vary according to the severity of seizure insult.

We investigated the time course of GFAP levels in the hippocampal formation during the first 24 h following soman intoxication in rats. GFAP mRNA expression was detected by in situ hybridization. Intense GFAP mRNA expression was present in the molecular layer of the dentate gyrus as early as 6 h after intoxication. This expression was comparatively lower in other dentate gyrus layers and hippocampal CA1, CA3 and CA4 areas and seemed to be related to excessive neuronal activity. Histopathological examination demonstrated that GFAP expression in dentate gyrus is not correlated with lesions. The high astrocytic reactivity in the molecular layer of the dentate gyrus is discussed in relation to the maintenance of the homeostasis of glutamate and of synaptic plasticity in this area during soman intoxication.

To explore memory impairments in temporal lobe epilepsy, we used two experimental models in the rats : (a) kainate-induced status epilepticus (SE) resulting in excitotoxic damage and in later spontaneous seizures ; and (b) amygdala kindling, known to induce no lesions (or only minor) and neuronal reorganization. Long-term effects of these models on memory were investigated with a spatial learning task in a radial-arm maze, and a social interaction test that implies degree of short-term memory. An histological analysis was made to determine neuronal damage or loss caused by epileptic activity in brain regions that could be related to memory functions. Kainate-induced epilepsy produced large memory deficits in animals tested 5 months after the injection. The rats showed severe lesions in amygdala and hippocampus and piriform and entorhinal cortex. Spatial memory was strongly diminished. The social memory test was severely impaired, probably due to the extent of amygdala injury, which is known to disturb social behavior. On the contrary, kindled rats showed no evident lesion in any brain region and displayed performances as good as those of controls in both tests. These experiments demonstrated that memory deficits appear to be related to the severity of neuronal damage in limbic areas, and the ability to develop seizures (permanence) is not solely responsible for these memory disturbances.

An organotypic culture system of anterior hypothalamic slices was developed for studying the secretory responses of corticotropin-releasing hormone (CRH) neurons to corticosteroid-catecholamine interactions. The standard culture medium included 5% horse serum containing 50 micrograms/l cortisol. In 1- to 3-day cultures, the tissue viability was demonstrated by the presence of arginine vasopressin immunolabeled perikarya and axons in the paraventricular nucleus and by sustained tissue concentrations of CRH (around 50 pg/mg protein). However, immunoreactive CRH neurons were not detectable in cultures in the standard medium. Exposure of cultures to high K+ (56 mM) in the medium induced a ten-fold increase in basal CRH release which was completely abolished in a Ca(2+)-free medium containing 2 mM EGTA. Noradrenaline (NA) triggered CRH release in a dose-dependent (1-20 microM) and time-dependent (0.5-6 h) manner. Removal of corticosteroids from the media by charcoal treatment led to (1) the visualization of immunolabelled CRH perikarya and fibers and a 55% rise in CRH content of the paraventricular nucleus tissue and (2) to a five-fold increase in CRH release. Both effects were reversed by supplementation of the culture medium with corticosterone (50 micrograms/l). Under steroid-free conditions, NA (1-10 microM) not only failed to induce CRH release, but strongly inhibited the consistent baseline in CRH release. This was reminiscent of a similar corticosteroid-dependent inversion of the NA effect on the hypothalamic-pituitary-adrenal axis described in vivo. Overall, these results are direct evidence of complex corticosteroid-catecholamine interrelationships as major regulatory factors of the hypothalamic-pituitary-adrenal axis.

The olfactory bulb (OB) kindling is a model of limbic secondary generalized epilepsy. Ten days after the completion of OB kindling, we have studied the long term effects of both electrode insertion and kindling on the binding of [3H]diazepam to crude mitochondrial fractions. On the one hand, we have shown that electrode implantation in sham-operated controls induced an obvious increase in benzodiazepine (BZD) receptor density (Bmax) only at the site of the electrode in comparison to sham-unoperated rats. These results might indicate an additional mechanism extending earlier observations reported by others, who have shown that prolonged electrode implantation induced changes in sham-operated and kindled rats. On the other hand, the long lasting effect of OB kindling on the binding parameters of [3H]diazepam was examined in the focus and in the hippocampus. The results indicate a bilateral increase of BZD receptors in the OB and an ipsilateral increase in the hippocampus. These changes might be a regulation phenomenon in response to a hyperexcitability state and to focal stimulations.

Distant damage, localized in the CA3 and CA1 areas, was observed in the hippocampus of rats as a consequence of status epilepticus (SE) induced by the injection of 2.5 nmol of kainic acid (KA) into the amygdala. In animals pretreated with an intraperitoneal injection of the non-competitive antagonist of the N- methyl- d -aspartate receptor, N -[1-(2-thienyl)cyclohexyl]-piperidine (TCP) (20 mg/kg), distant neuronal damage was reduced (CA1 neurons were always spared) whereas the rats still developed SE with an earlier onset. These results demonstrate the protective effect of TCP and confirm that epileptic activity and brain damage may be dissociated by NMDA receptor antagonists.

The anticonvulsive properties of a new compound: F1933 (Dulozafone) were investigated in the amygdala kindling model and compared with those of diazepam. Both of drugs protected fully kindled rats against generalized siezures but failed to suppress partial ictal events (amygdala afterdischarges and limbic seizures). The anticonvulsive action of F1933, administered at the ED 100 , was nearly reversed by the specific antagonist of benzodiazepines receptors: R015-1788 (Flumazenil), suggesting that the effect of F1933 is mediated by this receptor. These results also emphasize the usefulness of kindling to test antiepileptic drugs and to confirm their supposed profile of action.

The capacity of thienylcyclohexylpiperidine (TCP), a non-competitive blocker of the N-methyl- d -aspartate (NMDA) receptor, to counteract the convulsant, lethal, and neuropathological effects of 2 × LD50 of soman (an irreversible inhibitor of cholinesterase) was investigated in guinea-pigs treated by pyridostigmine and atropine sulphate. The effects of a weak dose of TCP (1 mg/kg) used in the present study globally reproduced those previously obtained with a higher dose (2.5 mg/kg; [Neurotoxicology 15 (1994) 837]): TCP was again most protective when given curatively within the first hour of soman-induced seizures. In this condition, (a) paroxysmal activity ceased in 10–20 min, (b) all the animals survived, (c) the majority of them recovered remarkably well and did not show any brain damage 24 h after the intoxication, and (d) the minimal duration of seizure activity normally required for producing soman-induced brain damage in other pharmacological environments was increased from 10 to 40 min to 80 min. Strikingly, when TCP was given 120 min after seizure onset, it failed to show any anticonvulsant activity but still provided neuroprotection in the hippocampus. The present study also gives additional evidence (see [Neurotoxicology 21 (4) (2000) 521]) that in soman poisoning, (a) the development of brain damage depends on the occurrence of ECoG seizures, (b) the topographical distribution of lesions depends on seizure duration, and (c) an increase of the relative power in the lowest (delta) frequency band might be a reliable marker of neuronal degradation. All these findings confirm that (a) glutamatergic NMDA receptors are involved in the mechanisms of soman-induced seizures and brain damage, (b) non-competitive antagonists of NMDA receptors might be promising candidates for post-treatment of soman poisoning, and (c) ECoG parameters from ECoG tracings and power spectrum might serve as useful external predictors for soman-induced neuropathological changes.

Previous studies have shown the successive expression of c-fos and hsp70 genes, especially in the hippocampal formation, during soman-induced seizures. In order to detect a possible link between the induction of these two genes, antisense strategies have been used. First, the ability of unilateral intrahippocampal infusion of c-fos antisense oligonucleotides to inhibit ipsilateral, seizure-related, c-FOS-like immunoreactivity, was verified. Second, induction of hsp70 mRNA was investigated using in situ hybridization. Unilateral inhibition of c-fos induction clearly reduced levels of hsp70 mRNA in the c-fos antisense-infused hippocampus relative to the non-infused contralateral side. Infusion of c-fos sense probe or vehicle did not affect bsp70 mRNA induction. This study suggests a role of c-FOS in regulating bsp70 mRNA induction.

Serotonin (5-HT) is involved in a large variety of physiological functions and it appears now that it could play a role in cognitive processes through the activation of 5-HT4 receptors. The present study was conducted to determine the effect of BIMU1, a mixed 5-HT4 agonist/5-HT3 antagonist on social olfactory recognition in rats, a behaviour test which has previously been shown to access short-term memory and to be sensitive to cholinergic drugs. This test is based on the investigation of an unfamiliar juvenile by an adult rat during two distinct 5-min presentations. At a 30-min delay after each presentation adults recognized the juvenile, whereas after a 2-hr delay all the adults had forgotten it. When administered intraperitoneally immediately after the first presentation, BIMU1 (10 mg/kg) enhanced short-term memory (i.e. recognition of the juvenile after a 2-hr delay). Ondansetron (10 and 100 micrograms/kg injected intraperitoneally), a 5-HT3 antagonist, had no significant effect on this form of memory. The effect of BIMU1 was antagonized by intraperitoneal injection of GR 125487, a very selective and potent 5-HT4 antagonist. The antagonistic effect was obtained at 1 and 10 mg/kg of GR 125487, but not at 0.1 mg/kg. It is certainly a specific effect on brain 5-HT4 receptors, since we determined a brain concentration of GR 125487 equal to 3.8 x 10(-7) M after the intraperitoneal injection of 10 mg/kg of this drug. This GR 125487 concentration is certainly sufficient to occupy all the 5-HT4 brain receptors (Kd = 10(-10) M) but not to occupy 5-HT3 receptors (Kd > 10(-6) M). The 5-HT4 specificity of the blockade by GR 125487 is further demonstrated by the fact that a 10-fold lower dose of GR 125487 (1 mg/kg) is also effective to inhibit the BIMU1 effect.

Processing of epileptic EEG is required for better understanding of the mechanisms underlying the generation and propagation of seizure electrical activity, as well as for mapping of epileptic foci in patients with intractable focal epilepsy who are candidates for surgery. Most processing methods applied to the EEG require linearity; but, before the question of linearity/non linearity is handled, the non stationary character of the EEG signal has to be tackled.

Neuronal loss and gliosis were detected in the rat hippocampus soon after unilateral intra-amygdala injection of kainate (KA) (2.5 nmol) while solid mossy fiber sprouting could be seen only fourteen days after this injection. Using this experimental model, we examined the metabotropic glutamate receptor (mGluR)-induced inositol phosphate (IP) formation in hippocampal synaptoneurosomes and slices. In synaptoneurosomes prepared from ipsilateral hippocampi fourteen days following injection, there were no significant changes in mGluR- and carbachol(CARB)-stimulated IPs syntheses when sham-operated and KA-injected animals were compared. In the corresponding hippocampal slices, significant increases of the mGluR responses mediated by ibotenate (IBO) and aminocyclopentane-trans-1,3-dicarboxylate (t-ACPD) were noted after KA application. The net stimulation values respectively expressed in a pair-wise fashion for buffer-injected control and KA-treated animals were IBO: 1,947 +/- 457 and 10,553 +/- 1,242; t-ACPD: 1,557 +/- 662 and 9,449 +/- 2,251 dpm/mg protein respectively. Significantly augmented mGluR responses in hippocampal slices were also measured at 7, 42 and 92 days after KA injection. There were, however, no significant increases in CARB-stimulated phosphoinositide hydrolysis in the hippocampal slices at all time-intervals after KA administration. These findings show that there are differences between the mGluR responses in hippocampal synaptoneurosome and slice preparations, suggesting the presence of two distinct populations of mGluR in each of these two models. The large specific increases in certain mGluR activities after KA-induced status epilepticus in hippocampal slices could represent one of the molecular mechanisms which underlie the profound morphological changes, in particular gliosis or mossy fiber sprouting, which follow the KA-induced status epilepticus.

Publisher Summary In cerebellar granule cells, endogenous production of NO tonically blocks N-methyl- D-aspartate (NMDA) receptors. Superoxide ions seem to be more efficient than NO at inducing NMDA neurotoxicity. Under experimental conditions, blocking NO formation did not prevent glutamate neurotoxicity in vitro or in vivo . On the contrary, complete depletion of NO synthesis increased the deleterious action of NMDA on neurons, probably by suppressing the negative feedback exerted by NO on NMDA receptors. In vitro studies showed that purified nitric oxide synthase can produce oxygenated free radicals such as superoxide ion when L-arginine concentrations are low. However, this was not the case under our experimental conditions, as indicated by the production of NO and cyclic guanosine monophosphate upon NMDA receptor stimulation, because neurons are usually not depleted in L-arginine. Moreover, under such conditions NO Arg did not suppress NMDA-induced superoxide ion production. Activation of phospholipase A 2 induced by NMDA receptor stimulation may be an important although not exclusive step in the generation of oxygen radicals and neuronal death.

Sleep of 8 narcoleptic and 8 control subjects was recorded under baseline (i.e., prior wakefulness 16 h) and after 24 h without sleep. During both baseline and recovery total sleep time and stage 2 non-REM sleep were significantly decreased in narcoleptic subjects. Slow wave activity (i.e., EEG power density in the range of 0.75-4.5 Hz) decayed exponentially during baseline and after sleep deprivation in both narcoleptic and control subjects. During both baseline and recovery EEG power density in delta and sigma frequencies in non-REM sleep was enhanced in narcoleptic subjects relative to controls. In REM sleep differences in the same direction were present in delta and beta frequencies. After sleep deprivation EEG power density in non-REM sleep was elevated in delta and some higher frequencies in both patients and controls, but the response to sleep deprivation was stronger in narcoleptic subjects. These data show that in narcoleptic subjects regulatory processes underlying non-REM sleep homeostasis are operative and indicate that the response to sleep deprivation is stronger than in control subjects.

The regulation of the binding sites of [3H]TCP, a non-competitive ligand of the N-methyl-D-aspartate (NMDA) receptor, was studied on membranes prepared from different CNS regions of amygdaloid-kindled rats. The high-affinity binding sites (KdH = 4.2-7.4 nM), identified as the NMDA-gated ion channels, were not affected by kindling or by a daily injection of TCP (5 mg/kg before each electrical stimulation) which prevented kindling. These results suggest that the NMDA receptors participate to the establishment and not to the permanence of kindling. Kindling increases the number of low affinity [3H]TCP binding sites in the hippocampus (+21%, P less than 0.01) without change of the affinity (KdL = 340 nM). In the striatum both KdL and BmaxL were increased (3.3-4.4 fold, P less than 0.001) in animals pretreated with TCP before each electrical stimulation for 20 days. These last results argue in favour of a function of the low-affinity [3H]TCP binding sites, the nature of which remains to be determined.

Competitive N- methyl- d -aspartate (NMDA) receptor antagonists are known to protect neurones against hypoglycaemic damage. We tested N-[1-(2-thienyl)cyclohexyl]piperidine (TCP), a non-competitive NMDA antagonist, in a recovery model of hypoglycaemic coma in the rat. Administered concomitantly with insulin, TCP shortened the latency of onset of electrocerebral silence, and failed to prevent striatal and dentate gyrus hypoglycaemia-induced injury. This effect is probably related to an increase in glucose consumption of neurones: TCP enhances energy metabolism in several brain structures, which could facilitate, at low blood glucose levels, the onset of isoelectricity, and hamper a putative neuro-protective effect of the drug.

The effects of bilateral high radiofrequency lesions of superior colliculus (SC) were studied on amygdala kindling. The results demonstrate that a selective destruction of the SC only slightly facilitated the development of kindling. However, the most remarkable effect was the increase of afterdischarge and motor seizure duration observed when SC-lesioned animals reached the generalized seizures. These data confirm that the superior colliculi participate in controlling the generalization of kindled seizures.

In order to restore a normal pattern of kindling, kindled rats, previously lesioned in the olfactory nuclei with 5,7-dihydroxytryptamine, were grafted with serotonin (5-HT) neurons in the right olfactory bulb and then implanted for kindling procedure. It was observed that complete 5-HT lesions accelerated the kindling profile, and that the transplants containing 5-HT neurons restored, in lesioned rats, quite normal parameters.

The effects of the bilateral and selective destruction of substantia nigra (SN) dopaminergic or locus coeruleus (LC) noradrenergic neurones, consecutive to a local injection of 6-hydroxydopamine, were studied on the development of amygdala kindling. Immunohistochemical controls of lesions were performed using selective dopamine (DA) or norepinephrine (NE) antibodies. The results demonstrated that a massive destruction of SN pars compacta neurones did not modify the rate of kindling development. Conversely, the lesions of LC neurones (sparing lateral tegmental nuclei) markedly facilitated the development of amygdala kindling. This effect was related to the extent of NE denervation. Together, these results suggest that DA is not strongly involved in the development of kindling, and that the nigrostriatal output does not play a major role in the generalization of kindled seizures. In contrast, they confirm an inhibitory influence exerted by LC noradrenergic ascending pathways on the development of kindling.

There are several lines of evidence that excitatory amino acids (EAA) receptors, which have a rather ubiquitous distribution in the CNS play a role in the genesis of epilepsy. Systemic or intracerebroventricular injections of EAA agonists (glutamate, NMDA, kainate, quisqualate) were all demonstrated to induce epilepsy (22), while their antagonists were potent antiepileptic or anticonvulsant agents in a wide variety of animal models (5,6). Furthermore, epileptic activities were often associated with an increase in the release of the putative endogenous transmitters aspartate and glutamate (7,15,29). There exist at least three different subclasses of EAA receptors (NMDA, quisqualate and kainate) and these multiple receptors may lead different responses to the same transmitter (8). In addition, it appears that ions are able to modulate their activation (18). Among these subclasses, most of the studies focused, in part because of the relative abundance of NMDA-antagonists, on the role of the NMDA-receptor which is mainly involved in the plasticity of the central nervous system and the generation of oscillatory activity (38). Several results indicate that it plays too a crucial role in epilepsy.

The occurrence of wet dog shakes (WDS) was studied during hippocampal kindling and amygdala kindling. Many WDS were observed after the first stimulation of the dorsal and ventral hippocampus. Their number rapidly increased to a maximal value (after five to six stimulations) and then progressively decreased during the development of hippocampal kindling. Their distribution during the afterdischarge (AD) was impaired by kindling. During amygdala kindling, WDS were observed only when the ADs attained a total duration of at least 50 s. In this case too, the repetition of stimulations was concomitant with a progressive decrease in the number of WDS. We suggest that the regression of the number of WDS may be considered as an additional criterion of the fully kindled state.

Brief exposure of cortical or hippocampal cell cultures to glutamate (500 μM) resulted in a progressive neuronal necrosis which is maximal 18–24 h later. Pretreatment of the cultures by a phencyclidine derivative: thienylphencyclidine (TCP), or the TCP precursor: GK86, or MK801 protected against glutamate toxicity. Non-competitive antagonists of N- methyl- d -aspartate receptors appear as potent tools for the in vitro protection of neuronal cells against excitatory amino acid toxicity.

gamma-Amino[2,3-3H]butyric acid ([3H]GABA) transport was investigated in hippocampal synaptosomes prepared from amygdala kindled rats. Kindling enhanced [3H]GABA uptake by 10-20%, while the Km of uptake and the kinetics of the release were unchanged. The dose response curve of the inhibition of [3H]GABA uptake by veratridine was altered by kindling: the K0.5 of inhibition and the Hill number increased and the curve became biphasic after a long period of stimulations. This effect was interpreted in terms of a modification of the functioning of the presynaptic fast Na+ channels which initially become more resistant to depolarization. In the long term, it appears that new Na+ channels develop that are more sensitive to the action of veratridine.

The role of serotonin (5-HT) in the kindling model of epilepsy was investigated by performing specific lesions of the 5-HT innervation at the level of the primary epileptogenic focus. We injected bilaterally 5,6-dihydroxytryptamine in the olfactory bulb (OB) of adult rats which were submitted to electrical stimulations of the OB until the occurrence of stage-5 seizures. Immunohistochemical controls of lesions were realized with a specific anti-5-HT antibody. Results revealed that the lesions facilitated the initital development of kindling (increase of afterdischarge duration and of kindling rate), suggesting that 5-HT terminals exert a modulatory effect on the propagation of the epileptic activity.

Wet dog shake behavior was studied in different models of epilepsy in the rat. Numerous wet dog shakes were associated with limbic seizures in the course of focal epilepsy induced by kindling stimulations or local injections of kainic or quisqualic acid and progressively disappeared during generalization. On the contrary, they were never observed in models of generalized epilepsy. This study suggests that the number of wet dog shakes may be an index of the progression of limbic seizures toward generalization.

Kindling patterns were compared in different regions of the hippocampus of the rat. The duration, morphology, and frequency of the electrical responses were different after stimulation of the dorsal and the ventral hippocampus, but these parameters showed the same evolution as kindling progressed. Comparison of the threshold intensity and of the kindling rate revealed some differences not only between dorsal and ventral hippocampus, but also within the dorsal hippocampus: The central layers had higher thresholds and longer kindling periods than the outer layers and the fimbria hippocampi. We suggest that stimulation of hippocampal efferents is responsible for the greater ease of kindling in the outer layers than in the central regions of this structure. The degree of connection of the different parts of the hippocampus with the amygdala and the influence of the intrinsic inhibitory GABAergic circuitry are discussed.

Alterations in γ-aminobutyric acid (GABA) metabolism have been investigated in the kindling model of epilepsy. Numerous generalized seizures were induced by amygdala-kindling stimulations in rats. One week after the last stimulation, there were no changes in GABA levels nor in the activity of enzymes responsible for the synthesis (glutamic acid decarboxylase) and catabolism (GABA transaminase and succinyl semialdehyde dehydrogenase). These results do not exclude other changes in GABA function as modifications of transport or receptors.

In response to NMDA receptor activation, hippocampal, striatal and cerebellar neurons synthesize nitric oxide (NO), which in turn elevates cGMP levels via guanylate cyclase. NO is increasingly being considered as a transsynaptic retrograde messenger, involved in neuronal plasticity. The effect of an inhibitor of NO synthase, L-NG-nitroarginine (NOArg), was studied on amygdala kindling and on kindled seizures in rats. NOArg increased kindling rate, particularly in its initial period, but did not modify seizure severity in previously kindled rats, although we have no definitive explanation for this effect. However, an enhanced post-synaptic excitability could be attributed to the blockade of the negative feed-back exerted by NO on the NMDA receptor.