K+ channel openers decrease seizures in genetically epileptic rats.
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Biomedical subjects
Publications and source records attributed to C Gottesmann.
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Intracerebroventricular injection into rats of mast-cell degranulating peptide (MCD), dendrotoxin I (DTXI) and 4-aminopyridine (4-AP), three blockers of a subclass of K+ channels, elicited epileptiform wave bursts and convulsions. Three different types of L-type Ca2+ channel inhibitors (+)PN 200-110, a 1,4-dihydropyridine, (-)D888, a phenylalkylamine, and fluspirilene, a diphenylbutylpiperidine, were potent blockers of the convulsant-induced hyperexcitatory effects when they were administered preventively. D-AP5, a N-methyl-D-aspartate antagonist, was active on the 4-AP-induced seizures but was without effect on the MCD- and dendrotoxin-induced seizures.
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In eleven acute precollicular rats, cortical and hippocampal EEG activity was recorded. Hippocampal theta activity of low frequency (mean 4.5 c/sec) was found in nine rats and in four occupied above 50% of the recording time. In contrast, in the cortex the synchronized EEG activity dominated. The electrical stimulation of the posterior hypothalamus induced the theta rhythm, or increased its frequency. The large amounts of theta activity in some rats suggests that the forebrain theta pacemakers, partly modulated by the posterior hypothalamus, are released from brain stem inhibitory influences.
The purpose of the experiment was to study the effects of psychological factors on slow brain potentials in relation to information processing and strategy establishment. Subjects were subjected to paired stimuli: A) two identical tone bursts (50 ms, 5000 Hz); B) two different stimuli the second (unconditioned) was a low pitched tone burst (50 ms, 500 Hz); C) only the warning stimulus was delivered to the subjects. In a first experiment, subjects (N = 10) were asked to detect and signal by a motor act the low pitched click (B); in a second experiment, subjects (N = 8) were to detect and signal in the same way the unconditioned tone burst omission (C). Results showed that the auditory event-related potentials (ERP) obtained in the two experiments presented two components: a negative wave (N150) followed by a positive one (P270). Solely, the late positive component differed in topography during the two situations. A fronto-central Contingent Negative Variation (CNV) appeared in all the conditions for the two experiments while a Post Imperative Negative Variation was often obvious in the first experiment.
Rats received a neonatal (at 4 days of age) intracisternal injection of 5,7-dihydroxytryptamine which eliminates serotonin (5-HT) throughout adulthood. Sleep recordings, performed on these rats at adult age, demonstrated significant decreases in paradoxical sleep. Dissociated fetal 5-HT cell suspensions transplanted in the IVth ventricle of these rats restored paradoxical sleep. However, fetal neuronal noradrenergic or cholinergic transplants did not restore paradoxical sleep. These results suggest that paradoxical sleep is directly or indirectly mediated through serotoninergic mechanisms.
The intercollicular transected preparation opened a rich field for investigations of sleep-wake mechanisms. Initial results showed that brain stem ascending influences are essential for maintaining an activated cortex. It was subsequently shown that the forebrain also develops activating influences, since EEG desynchronization of the cortex reappears in the chronic cerveau isolé preparation, and continuous or almost continuous theta rhythm is able to occur in the acute cerveau isolé preparation. A brief "intermediate stage" of sleep occurs during natural sleep just prior to and after paradoxical sleep. It is characterized by cortical spindle bursts, hippocampal low frequency theta activity (two patterns of the acute cerveau isolé preparation) and is accompanied by a very low thalamic transmission level, suggesting a cerveau isolé-like state. The chronic cerveau isolé preparation also demonstrates that the executive processes of paradoxical sleep are located in the lower brain stem, while the occurrence of this sleep stage seems to be modulated by forebrain structures.
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The mast cell-degranulating peptide (MCD) isolated from bee venom has been found previously to have receptor sites in rat brain. Behavioral and electrocorticographic responses following intracerebroventricular injections of various doses of MCD have been analyzed. MCD produced a quasi-permanent hippocampal theta rhythm in the motionless animal alternating with epileptiform spike waves and paroxystic seizures. At a dose of 70 pmol seizures occurred for half of the treated rats. At a dose of 100 pmol generalized paroxystic crises were observed for all the rats. These effects were not antagonized by naloxone, morphine, diazepam and progabide. Rats recovered 24 h after a 100 pmol injection of MCD. A second ipsilateral injection to these rats showed the occurrence of a desensitization phenomenon. Desensitization was not observed when the second injection was contralateral. These physiological responses were studied in relation with a biochemical approach on membrane sites of action of MCD using [125I]MCD and their behavior in the desensitization process. The target of [125I]MCD is the ipsilateral hippocampus. Recovery from MCD effects was not due to MCD degradation. Desensitization was not due to down-regulation of the MCD receptor level.
Ten young men underwent a sleep deprivation of 48 h which resulted in a 19 percent decrease of beard-hair growth. This effect, reflecting the lowering of protein synthesis during sleep deprivation, was presumably related to hormonal disturbance, namely depression of growth hormone release, decrease of dihydroxytestosterone availability or increase of sympathetic tone and/or corticoids.
The positive components 1 and 2 of the averaged field response induced in the somesthetic S1 cortex by submaximal stimulation of cortical radiation and supramaximal stimulation of lemniscus medialis showed non-existent amplitude variability whereas the dispersion was significant for components 3, 4 and 5. The same stimulus delivered at a short intershock interval only induced waves 1 and 2 without any amplitude variability, the three following ones being under complete refractoriness. These results suggest a presynaptic origin of component 2.
The aim of this research was to study brain information processing during waking, deep slow sleep (stage IV) and paradoxical sleep (stage V) in humans, by using as a clue endogenous components of the sensory evoked potential, the emitted potential and the contingent negative variation (CNV). Eight subjects underwent three kinds of mixed auditory stimulus couples: (a) SI-SII: 2 identical clicks (50 msec, 5000 Hz); (b) SI-SIII: SIII (50 msec, 500 Hz) different from SI, was during waking, the target stimulus; (c) SI followed by an omitted click. During sleeping, the situation was used without motor response. The contingent negative variation was clearly observed during waking and paradoxical sleep as the evoked potential whose morphology during deep slow sleep was similar to K complexes. The emitted potential was obtained in four subjects out of seven during paradoxical sleep. These results suggest that during wakefulness, the discrimination of an unconditional stimulus involves a conditioning establishment revealed by the CNV and the emitted potential. The fact that the emitted potential and CNV were unavailable during stage IV is an argument in favor of the hypothesis that the conditioning effects disappear during deep slow sleep. The occurrence of CNV and emitted potential during the paradoxical stage of sleep, suggests that a conditioning established during waking can appear during this stage of sleep.
By a method of automatic on-line scoring of sleep-waking stages in the rat, a significant decrease of the mean circadian level of paradoxical sleep and a significant increase of light slow sleep were shown in adult animals after neonatal disruption of serotoninergic system by intracisternal injection of 100 micrograms of 5.7-dihydroxytryptamine, when compared to an aged matched sham group. The level of paradoxical sleep was restored in the neurotoxin-treated rats by an intracisternal injection of a suspension of foetal raphe neurons.
The rat and cat show just prior and sometimes after paradoxical sleep a short-lasting behavioral stage characterized by: i) frontal cortex high amplitude spindle bursts and low frequency theta activity in the dorsal hippocampus, and ii) the lowest ventrobasal complex transmission level of all sleep-waking stages. The duration of this "intermediate" stage is increased at the expense of paradoxical sleep by low doses of barbiturate. The intercollicular "cerveau isolé" preparation shows for hours the electrophysiological patterns of the intermediate stage. It is concluded that the intermediate stage of sleep corresponds to a forebrain massive deafferentation process leading to a functional disconnecting from the brainstem. For the survival of the species it is understandable that this behavioral stage is necessarily short lasting.
Cortical and hippocampal EEG activity was analysed in cerveau isolé and and pretrigeminal rats. In the acute stage, waking EEG patterns were absent in the cerveau isolé, whereas sleep EGG patterns were absent in the preparations. However, already on the second day the EEG waking sleep cycle recovered in the majority of rats. Paradoxically, stimuli directed to the caudal part of the preparations evoked stronger cortical and hippocampal EEG arousal than olfactory and visual stimuli. The rats exhibited some locomotor and grooming behaviour and could be fed orally. It is concluded that the activity of the isolated cerebrum of the rat is similar to that of cat preparations, but that functions of the caudal neuraxis are superior in rats.
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The two kinds of sleep spindles, previously described in the rat, were studied in intact animals, cerveau isole preparations and unilaterally neodecorticated rats. The anterior (frontal) spindles reach their maximum during deep slow sleep, when accompanied by theta activity, during the so-called intermediate stage which occurs just before and after paradoxical sleep. This stage is extended by low doses of barbiturate and similar patterns are induced by an intercollicular transection. The anterior spindles are suppressed by unilateral nedecortication and become abortive on contralateral hemisphere. The posterior ones, larger when recorded in the dorsal hippocampus than an the occipital cortex precede the appearance of the theta activity of intermediate stage. They are absent when the theta rhythm is present, during the long-continued intermediate stage under barbiturate ad in the cerveau isole preparation; but an unilateral neodecortication does not prevent the occurrence of posterior spindles on the white matter. Thus, during deep slow sleep, the rat shows both frontal cortex spindles, fully spread out during intermediate stage, and posterior spindles, probably originating from structures implied in the theta genesis and heralding the occurrence of this rhythmic slow activity.
Cortical and hippocampal EEG activity was analysed in 14 cerveau isole and 8 pretrigerninal rats. In the acute stage, waking EEG patterns were absent in the cerveau isole, whereas sleep EEG patterns were absent in the pretrigeminal preparations. However, already on the second day the EEG waking-sleep cycle recovered in the majority of rats. Paradoxically, stimuli directed to the caudal part of preparations evoked stronger cortical and hippocampal EEG arousal than olfactory and visual stimuli. The behavior of the caudal part was observed in 25 preparations. Although in abortive form, the rats did show some locomotor and grooming behavior, and could be fed orally. The peripheral events of paradoxical sleep appeared only on the fourth or fifth day of survival of the cerveau isole rats. It is concluded that the activity of the isolated cerebrum of the rat is similar to that of cat preparations, but that functions of the caudal neuraxis are superior in rats.