Pathophysiological mechanisms of genetic absence epilepsy in the rat.

Generalized non-convulsive absence seizures are characterized by the occurrence of synchronous and bilateral spike and wave discharges (SWDs) on the electroencephalogram, that are concomitant with a behavioral arrest. Many similarities between rodent and human absence seizures support the use of genetic rodent models, in which spontaneous SWDs occur. This review summarizes data obtained on the neurophysiological and neurochemical mechanisms of absence seizures with special emphasis on the Genetic Absence Epilepsy Rats from Strasbourg (GAERS). EEG recordings from various brain regions and lesion experiments showed that the cortex, the reticular nucleus and the relay nuclei of the thalamus play a predominant role in the development of SWDs. Neither the cortex, nor the thalamus alone can sustain SWDs, indicating that both structures are intimely involved in the genesis of SWDs. Pharmacological data confirmed that both inhibitory and excitatory neurotransmissions are involved in the genesis and control of absence seizures. Whether the generation of SWDs is the result of an excessive cortical excitability, due to an unbalance between inhibition and excitation, or excessive thalamic oscillations, due to abnormal intrinsic neuronal properties under the control of inhibitory GABAergic mechanisms, remains controversial. The thalamo-cortical activity is regulated by several monoaminergic and cholinergic projections. An alteration of the activity of these different ascending inputs may induce a temporary inadequation of the functional state between the cortex and the thalamus and thus promote SWDs. The experimental data are discussed in view of these possible pathophysiological mechanisms.

[Thromboprophylaxis in neurosurgery and head trauma]. / Thromboprophylaxie en neurochirurgie et en neurotraumatologie intracrânienne.

The incidence of deep vein thrombosis (DVT) is between 20 and 35% using contrast venography, with a rate of symptomatic DVT between 2.3 and 6% in neurosurgery without any prophylaxis. The risk of DVT is poorly evaluated in head injured patients but is around 5%. Specific risk factors in neurosurgery are: a motor deficit, a meningioma or malignant tumour, a large tumour, age over 60 years, surgery lasting more than 4 hours, a chemotherapy. The benefit of mechanical methods or low molecular weight heparin (LMWH) for the prevention of DVP in neurosurgery is demonstrated (grade A). Each method decreases the risk by about 50%. A postoperative prophylaxis with a LMWH does not seem to increase the risk of intracranial bleeding (grade C). There is no demonstrated benefit to begin a prophylaxis with LMWH before the intervention. The duration of the prophylaxis is 7 to 10 days but this has not been scientifically determined.

[Thromboprophylaxis in elective spinal surgery and spinal cord injury]. / Thromboprophylaxie en chirurgie rachidienne traumatologique et non traumatologique.

The risk of deep vein thrombosis (DVT) after spinal cord injury is very high. Without prophylaxis the incidence of DVT using venography is 81% and the risk of symptomatic DVT is between 12 and 23%. The risk is much lower in elective spine surgery. After discectomy or laminectomy on less than two spine levels, the risk of DVT is less than 1%. After spinal fusion or extended laminectomy, the risk can be estimated between 0.3 and 2.2%. A prophylaxis is recommended for all patients after spinal cord injury (grade A). The association of a mechanical method and heparin is recommended (grade B). The duration of prophylaxis is 3 months in patients with a motor deficit (grade C). No prophylaxis is recommended after discectomy or limited laminectomy in patients without additional risk factors. Mechanical methods are recommended after spinal fusion or extended laminectomy. For patients with additional risk factors a low molecular weight heparin is recommended.

[Prevention of venous perioperative thromboembolism in ENT and maxillofacial surgery]. / Prévention de la maladie thromboembolique veineuse périopératoire en chirurgie ORL et maxillofaciale.

There are few studies of poor methodological quality on the risk of thromboembolism in head and neck surgery. The incidence of symptomatic deep vein thrombosis is estimated between, 0.1% and 0.6%. The patient's risk factors (cancer, alcoholism, smoking, malnutrition) determine for the assessment of the potential benefit of thromboembolism prophylaxis. No method can be recommended based on the literature. In patients receiving anticoagulant therapy undergoing superficial head and neck surgery or dental extraction, the literature suggest to continue anticoagulation throughout the perioperative period.

Mapping of cerebral blood flow changes during audiogenic seizures in Wistar rats: effect of kindling.

The quantitative autoradiographic [14C]iodoantipyrine technique was applied to the measurement of rates of local cerebral blood flow (LCBF) during audiogenic seizures in Wistar AS rats belonging to a genetic strain selected at the Centre de Neurochimie (Strasbourg, France) for their sensitivity to sound. Seizures were elicited in native rats never exposed to sound (single audiogenic seizures) or in rats previously exposed to 10-40 seizure-inducing sound stimulations until generalization of the seizure to forebrain areas (referred to as "kindled animals"). During single audiogenic seizures, rates of LCBF increased over control values in all areas but the genu of the corpus callosum. The highest increases in LCBF (180-388%) were recorded in the inferior and superior colliculus, reticular formation, monoaminergic cell groupings, especially the substantia nigra, posterior vegetative nuclei, and many thalamic and hypothalamic regions. The lowest increases were seen in forebrain limbic regions and cortical areas. In kindled animals, LCBF rates increased over control levels in 67 areas of the 75 studied. LCBF increases were generally of a lower amplitude in kindled than in naive rats. Differences between the two groups of seizing rats were located mostly in brain-stem regions, mainly the inferior colliculus, reticular formation, substantia nigra, and posterior vegetative nuclei. Conversely, rates of LCBF were similar in forebrain areas of naive and kindled animals. In conclusion, the present data show that there is a good correlation between the structures known to be involved in the expression of audiogenic seizures (inferior colliculus, reticular formation, substantia nigra mainly) and the large increase in LCBF during single audiogenic seizures, while rates of LCBF increase to a lesser extent in forebrain areas not involved in this type of seizures. The circulatory adaptation to kindled seizures is rather a decreased response in brain-stem regions and no change in the forebrain, although the kindling process induces a generalization of the seizure from brain-stem to anterior regions.

Absence seizures induce a decrease in cerebral blood flow: human and animal data.

Our previous studies on cerebral metabolic activity in genetic absence epilepsy rats from Strasbourg (GAERS) were in favor of decreased functional activity during absences and normal or increased interictal activity. To ascertain that hypothesis, in the present study we performed continuous measurements of CBF in both children with typical absence epilepsy and GAERS, using Doppler ultrasonography and laser-Doppler flowmetry, respectively. CBF fluctuations during absences were recorded in four children between 5 and 6 years of age and 16 adult GAERS. In both children and animals, CBF measured in the middle cerebral artery and cortical capillaries, respectively, significantly decreased by a median value of 20-24% under basal levels during spontaneous absences. In GAERS, CBF levels were continuously decreased during haloperidol-induced absence status epilepticus, while they were not affected by ethosuximide. Conversely, convulsive seizures induced in rats either by kainate or picrotoxin led to a 175-664% increase in CBF levels. In conclusion, the present data show that during spontaneous absences, CBF decreases under basal levels in both cortical capillaries (GAERS) and the middle cerebral artery (children). Moreover, these fluctuations occur in vessels with normal vascular reactivity, are not mediated by changes in PO2, PCO2, or arterial blood pressure, and represent rather a response to reduced metabolic demand.

Dietary cholesterol is secreted in intestinally derived chylomicrons during several subsequent postprandial phases in healthy humans.

BACKGROUND: The process of intestinal absorption and chylomicron resecretion of dietary cholesterol in humans is poorly understood. OBJECTIVE: The present study aimed to test the hypothesis that dietary cholesterol ingested during a given meal is resecreted into chylomicrons (and plasma) during several subsequent postprandial periods. DESIGN: Seven healthy subjects ingested 3 comparable mixed test meals (at 0, 8, and 24 h) containing a given amount of fat (49 g) and cholesterol (157 mg); blood samples were taken 3 and 6 h after each test meal and 48 and 72 h after the beginning of the experiment. Heptadeuterated dietary cholesterol was present in the first test meal only, enabling its specific determination with use of gas chromatography-mass spectrometry. Chylomicrons, LDL, and HDL were isolated and lipids were quantified. RESULTS: In apolipoprotein B-48-containing chylomicrons, deuterated cholesterol concentrations were moderate after the first meal (1.3 x 10(-4) mmol/L), reached a maximum after the second meal (2.4 x 10(-4) mmol/L), and were still elevated after the third meal (1.7 x 10(-4) mmol/L). In plasma, LDL and HDL cholesterol enrichment in deuterated cholesterol was lower than in chylomicrons and plateaued after 24--48 h. Estimates of newly secreted exogenous deuterated cholesterol in chylomicrons indicate that 30.7%, 55.2%, and 14.1% of the total was secreted after the first, second, and third meals, respectively. CONCLUSION: Ingested dietary cholesterol is secreted by the small intestine in chylomicrons into the circulation during > or =3 subsequent postprandial periods in healthy humans. This likely results from a complex multistep intestinal processing of cholesterol with dietary fat as a driving force.

Effects of gamma-hydroxybutyrate and gamma-butyrolactone derivates on spontaneous generalized non-convulsive seizures in the rat.

The effects of derivatives of gamma-hydroxybutyrate (GHB) and gamma-butyrolactone were examined in Wistar rats from a strain in which spontaneous spike-and-wave discharges can be recorded electroencephalographically. For each compound, the effects were compared to those obtained in rats from a strain without spontaneous seizures. Administration of GHB (62.5-375 mg/kg, i.p.) increased, in a dose-dependent manner, the duration of spontaneous spike-and-wave discharges. In non-epileptic rats, this compound (250 and 375 mg/kg) induced bursts of spikes of a lower frequency and smaller amplitude than spontaneous spike-and-wave discharges. Similar results were obtained in both strains, respectively, after injection of gamma-butyrolactone (85-170 mg/kg, i.p.). This latter compound, however, showed greater potency in its epileptogenic effects than GHB. Administration of trans gamma-hydroxycrotonic acid (up to 1000 mg/kg, i.p.), a semi-rigid analogue of GHB was without any effect in both strains of rats. Injection of gamma-crotonolactone (42.5-170 mg/kg, i.p.), suppressed the spike-and-wave discharges in epileptic rats and had no effect in non-epileptic animals. These results confirm the similarities between seizures induced by GHB and spontaneous spike-and-wave discharges in the rat. The neural mechanism of the epileptogenic effect of GHB is discussed.

Effects of drugs affecting dopaminergic neurotransmission in rats with spontaneous petit mal-like seizures.

Drugs interacting with dopaminergic neurotransmission were studied on a model of genetic petit mal-like seizures in a strain of Wistar rats. Dopamine participates in the control of seizures in this model, as in other models of petit mal or of genetic epilepsy. Mixed dopaminergic D1/D2 agonists: L-DOPA, apomorphine, amphetamine and nomifensine, gave dose-dependent reductions of the duration of spike and wave discharges. Mixed D1/D2 antagonists: haloperidol, flupentixol and pimozide, caused dose-dependent increases of duration of spike and wave discharges. The findings with specific agonists or antagonists of D1 or D2 receptors did not reveal clearly the respective roles of these receptors in controlling the spike and wave discharges. The D2 agonists, lisuride and pergolide, had no effect on spike and wave discharges, except at toxic doses; bromocriptine decreased the duration of the discharges, but without clear-cut dose-dependency. The D2 antagonists: sulpiride and tiapride, had no effect. The D1 agonist SKF 38393 decreased duration of the spike and wave discharges in a dose-dependent manner. The D1 antagonist SCH 23390 had a biphasic effect: increasing the duration of spike and wave discharges at small doses and decreasing it at large doses. These results suggest that the simultaneous stimulation or inhibition of both receptors, D1 and D2, is necessary for influencing spike and wave discharges in this model.

Medium-voltage 5-9-Hz oscillations give rise to spike-and-wave discharges in a genetic model of absence epilepsy: in vivo dual extracellular recording of thalamic relay and reticular neurons.

In humans with absence epilepsy, spike-and-wave discharges develop in the thalamocortical system during quiet immobile wakefulness or drowsiness. The present study examined the initial stage of the spontaneous development of spike-and-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg. Bilateral electrocorticograms were recorded in epileptic and non-epileptic rats under freely moving and undrugged conditions and under neuroleptanalgesia. Short-lasting episodes of medium-voltage 5-9-Hz (mean=6-Hz) oscillations usually emerged spontaneously from a desynchronized electrocorticogram and in bilateral synchrony in both rat strains. These oscillations were distinguishable from sleep spindles regarding their internal frequency, duration, morphology, and moment of occurrence. Spontaneous spike-and-wave discharges developed from such synchronized medium-voltage oscillations, the spike-and-wave complex occurring at the same frequency as the 5-9-Hz wave. Because the thalamus is thought to play a significant role in the generation of spike-and-wave discharges, dual extracellular recording and juxtacellular labelling of relay and reticular neurons were conducted to study the thalamic cellular mechanisms associated with the generation of spike-and-wave discharges. During medium-voltage 5-9-Hz oscillations, discharges of relay and reticular cells had identical patterns in epileptic and non-epileptic rats, consisting of occasional single action potentials and/or bursts (interburst frequency of up to 6-8 Hz) in relay cells, and of rhythmic bursts (up to 12-15 Hz) in reticular neurons, these discharging in the burst mode almost always before relay neurons. The discharge frequency of reticular bursts decelerated to 6 Hz by the beginning of the spike-and-wave discharges. During these, relay and reticular neurons usually fired in synchrony a single action potential or a high-frequency burst of two or three action potentials and a high-frequency burst, respectively, about 12 ms before the spike component of the spike-and-wave complexes. The frequency of these corresponded to the maximal frequency of the thalamocortical burst discharges associated with 5-9-Hz oscillations. The patterns of relay and reticular phasic cellular firings associated with spike-and-wave discharges had temporal characteristics similar to those associated with medium-voltage 5-9-Hz oscillations, suggesting that these normal and epileptic oscillations are underlain by similar thalamic cellular mechanisms. In conclusion, medium-voltage 5-9-Hz oscillations in the thalamocortical loop give rise to spike-and-wave discharges. Such oscillations are not themselves sufficient to initiate spike-and-wave discharges, meaning that genetic factors render thalamocortical networks prone to generate epileptic electrical activity, possibly by decreasing the excitability threshold in reticular cells. While these GABAergic neurons play a key role in the synchronization of glutamatergic relay neurons during seizures, relay cells may participate significantly in the regulation of the recurrence of the spike-and-wave complex. Furthermore, it is very likely that synchronization of relay and reticular cellular discharges during absence seizures is generated in part by corticothalamic inputs.

Nucleus basalis lesions suppress spike and wave discharges in rats with spontaneous absence-epilepsy.

Cholinergic drugs were shown to affect spike and wave discharges in a selected strain of Wistar rats with generalized non-convulsive absence epilepsy, named GAERS (Genetic Absence Epilepsy Rats from Strasbourg). The involvement of cholinergic transmission from the nucleus basalis in the control of absence seizures in GAERS was investigated in the present study, by examining the effects of unilateral excitotoxic lesions of this nucleus on the occurrence of spike-wave discharges. Ibotenate (0.01 M) and quisqualate (0.03 and 0.06 M)-induced lesions of the nucleus basalis suppressed spike-wave discharges in the cortex ipsilateral to the lesion. The suppression was associated with a disappearance of both acetylcholinesterase-fibres in the cerebral cortex and choline acetyltransferase immunopositive neurons within the nucleus basalis. Concomitantly, the background electroencephalographic activity was slowed. These results suggest that cholinergic innervation of the cerebral cortex by the nucleus basalis is involved in the occurrence of generalized non-convulsive seizures, in relation to the control of cortical activation.

Mesopontine cholinergic control over generalized non-convulsive seizures in a genetic model of absence epilepsy in the rat.

Pharmacological data have shown that the cholinergic transmission participates in the control of spike-and-wave discharges in rats with genetic absence epilepsy. The corticothalamic circuitry which generates spontaneous spike-and-wave discharges, the electroencephalographic expression of absence seizures, receives important cholinergic inputs from two distinct sources: (i) the nucleus basalis projecting mainly to the cortex and (ii) the pedunculopontine and laterodorsal tegmental nuclei providing cholinergic afferents to the thalamus. In the present study, the involvement of the cholinergic mesopontothalamic projections in the control of spike-and-wave discharges was investigated. Activation of cell bodies in the pedunculopontine and laterodorsal tegmental nuclei, by local microinjections of non-toxic doses of kainate (20 pmol/side) or picrotoxin (66 pmol/side), suppressed spike-and-wave discharges. Similar effects were produced by direct cholinergic activation of the ventrolateral part of the thalamus: intrathalamic microinjections of carbachol (0.7-2.8 pmol/side), a cholinergic receptor agonist, resulted in a dose-dependent suppression of spike-and-wave discharges. This suppression was partially reversed by a simultaneous microinjection of an equimolar dose of scopolamine, a muscarinic receptor antagonist. Electrolytic or neuroexcitotoxic lesions of the pedunculopontine and laterodorsal tegmental nuclei did not modify spike-and-wave discharges. These results suggest that the cholinergic mesopontine projection to the thalamus exerts a phasic inhibitory control of generalized non-convulsive epileptic seizures.

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.

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.

Involvement of the nigral output pathways in the inhibitory control of the substantia nigra over generalized non-convulsive seizures in the rat.

Activation of GABAergic transmission within the substantia nigra has been shown to suppress several forms of generalized seizures in experimental models of epilepsy. More especially, such pharmacological manipulations suppress spontaneous and chemically-induced generalized non-convulsive seizures in the rat. The aim of the present study was to examine the role of the dopaminergic and GABAergic thalamic and collicular nigral outputs in this antiepileptic effect. For this purpose, we examined the effects of output destruction on the antiepileptic effect of intranigral injections of a GABA agonist or pharmacological blockade of the neurotransmission at the nerve terminal level in rats with spontaneous absence seizures. After selective destruction of dopaminergic neurons within the substantia nigra with 6-hydroxydopamine (5 micrograms/side) or hemisection of the ascending nigral output, bilateral intranigral injection of muscimol (2 ng/side) still significantly suppressed generalized non-convulsive seizures. Bilateral lesioning of the ventromedial nucleus of the thalamus did not abolish the antiepileptic effects of intranigral muscimol (2 ng/side) and the GABA antagonist, picrotoxin, when given into this thalamic nucleus (10 ng/side) also failed to induce suppression of spike and wave discharges. The antiepileptic effects of intranigral injection of muscimol (2 ng/side) was reversed by bilateral electrolytic lesions of the superior colliculus. Blockade of the GABAergic transmission at this level with picrotoxin (40 ng/side) significantly suppressed generalized non-convulsive seizures. Finally, excitation of collicular cell bodies with low doses of kainic acid (4 and 8 ng/side) also resulted in a suppression of spike and wave discharges. These results demonstrate that the GABAergic nigrocollicular pathway is critical for the inhibitory control of the substantia nigra over generalized non-convulsive seizures. The data further suggest that antiepileptic effects observed following potentiation of GABAergic transmission in the substantia nigra result from a disinhibition of collicular cell bodies.

The amygdala is critical for seizure propagation from brainstem to forebrain.

Audiogenic seizures, a model of brainstem epilepsy, are characterized by a tonic phase (sustained muscular contraction fixing the limbs in a flexed or extended position) associated with a short cortical electroencephalogram flattening. When sound-susceptible rats are exposed to repeated acoustic stimulations, kindled audiogenic seizures, characterized by a clonic phase (facial and forelimb repetitive jerks) associated with cortical spike-waves, progressively appear, suggesting that repetition of brainstem seizures causes a propagation of the epileptic discharge toward the forebrain. In order to determine the structures through which this propagation occurs, four kinds of experiments were performed in non-epileptic rats and in sound-susceptible rats exposed to single or repeated sound stimulations. The following results were obtained: (I) Electrical amygdalar kindling was similar in non-epileptic and naive-susceptible rats, but was facilitated in sound-susceptible rats submitted to 40 acoustic stimulations and presenting kindled audiogenic seizures. (2) Audiogenic seizures induced an increase in [(14)C]2-deoxyglucose concentration in the amygdala after a single seizure, and in the amygdala, hippocampus and perirhinal and piriform cortices after a kindled audiogenic seizure. (3) A single audiogenic seizure induced the expression of c-Fos protein mainly in the auditory nuclei. A few cells were stained in the amygdala. After 5-10 audiogenic seizures, a clear staining appeared in the amygdala, and perirhinal and piriform cortices. The hippocampus expressed c-Fos later, after 40 audiogenic seizures. (4) Injection of lidocaine into the amygdala did not modify single audiogenic seizures, but suppressed myoclonias and cortical spike-waves of kindled audiogenic seizures. Similar deactivation of the hippocampus failed to modify kindled audiogenic seizures. Taken together, these data indicate a critical role for the amygdala in the spread of audiogenic seizures from brainstem to forebrain.

Prolactin-releasing peptide (PrRP) promotes awakening and suppresses absence seizures.

Prolactin releasing peptide (PrRP) is a recently identified neuropeptide that stimulates prolactin release from pituitary cells. The presence of its receptor outside the hypothalamic-pituitary axis suggests that it may have other functions. We present here evidence that PrRP can modulate the activity of the reticular thalamic nucleus, a brain region with prominent PrRP receptor expression that is critical for sleep regulation and the formation of non-convulsive absence seizures. Intracerebroventricular injection of PrRP (1-10 nmol) into sleeping animals significantly suppresses sleep oscillations and promotes rapid and prolonged awakening. Higher concentrations of PrRP (10-100 nmol) similarly suppress spike wave discharges seen during absence seizures in genetic absence epilepsy rats from Strasbourg, an animal model for this disorder. In concordance with these findings, PrRP suppressed evoked oscillatory burst activity in reticular thalamic slices in vitro. These results indicate that PrRP modulates reticular thalamic function and that activation of its receptor provides a new target for therapies directed at sleep disorders and absence seizures.

Repetitive electroconvulsive seizures induce activity of c-Jun N-terminal kinase and compartment-specific desensitization of c-Jun phosphorylation in the rat brain.

Electroconvulsive seizures (ECS) are used for therapy of pharmacoresistent depression and are supposed to induce long-lasting neuronal alterations in morphology and gene expression. In this study, we have investigated the phosphorylation of the transcription factor protein c-Jun at its serine 73 residue by immunohistochemistry and the activity of the c-Jun N-terminal kinase 1 (JNK1) by immunocomplex assay following repetitive ECS in adult rats. In untreated controls, nuclear c-Jun immunoreactivity, but not N-terminal phosphorylation, was present in a variety of neuronal populations including the hippocampus, the temporobasal cortex and the amygdalar complex. Daily ECS for 1, 5 or 10 days (1x, 5x or 10x ECS) did not alter the expression of c-Jun but caused a substantial N-terminal phosphorylation of c-Jun (phospho-c-Jun). Nuclear phospho-c-Jun immunoreactivity was maximal within 15 min following ECS, and became absent after 30 min. The highest levels of phospho-c-Jun labeling were found after 1x ECS in the amygdalar complex, the dorsomedial hypothalamus and the piriform cortex. The inducibility of c-Jun N-terminal phosphorylation was preserved in the medial amygdala and piriform cortex, but significantly declined in the basal amygdala and medial hypothalamus with progressive ECS stimulation. One single ECS 3 or 5 days following 10x ECS yielded a pattern of phospho-c-Jun as seen following 10x ECS; thus, a lag of 5 days was not sufficient to provoke the initial level of N-terminal phosphorylation of c-Jun. In the rostral hippocampus, c-Jun was not phosphorylated at any investigated time inspite of its high constitutive expression. In some contrast with this compartment-specific phosphorylation of c-Jun, immunocomplex assays revealed that the JNK1 activity was strongly enhanced in both amygdala and hippocampus. Our findings demonstrate that rapid JNK activation and phosphorylation of c-Jun as stand-by transcription factor characterize the beginning of neuroplastic changes, e.g., following ECS, a classic treatment of mental disorders. The N-terminal phosphorylation is compartment specific and can habituate following repetitive stimulation suggesting that the differential activation of the JNK/c-Jun axis is part of the neuronal strategy to integrate transynaptic excitation.

Gabaergic modulation of mouse-killing in the rat.

When GABA-potentiating compounds were administered IP to rats with prior experience of mouse-killing behaviour, a reduction of killing was observed with gamma-vinyl GABA (200 and 400 mg/kg) and nipecotic acid amide (400 mg/kg), while no significant effect was noted following injection of dipropylacetate or THIP. The inhibitory effects of gamma-vinyl GABA and nipecotic acid amide were not reversed by subsequent injection of picrotoxin and were associated with sedation as observed in open field and actograph tests. When GABA-potentiating compounds were administered to food-deprived rats exposed for the first time to a mouse (initial elicitation), administration of gamma-vinyl GABA, dipropylacetate, nipecotic acid amide or THIP increased the incidence of mouse-killing behaviour. Conversely, the incidence of mouse-killing under the same conditions was reduced following injections of picrotoxin. These results do not support the hypothesis that the general activation of GABAergic mechanisms inhibits mouse-killing behaviour in rats. On the contrary, data obtained in naive animals suggest that potentiation of these mechanisms actually facilitates the initial elicitation of this behaviour.

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.