Convulsive Threshold Research Articles

Kainic-acid-induced seizures: A developmental study

Developmental dose-response curves for kainic-acid-induced seizures were generated in rats. Rats at 15–18 days (pups), 33–37 days (pubescents) and over 90 days (adults) were administered kainic acid intraperitoneally. Seizures were elicited in all 3 age groups, but some of the behavioral manifestations differed in the pups. This group also had the lowest convulsive threshold, the most severe seizures and the highest mortality. Forelimb convulsions and status epilepticus were associated with the occurrence of necrotic lesions in the adults and pubescents but not in the pups. Deoxyglucose (DG) autoradiographic studies of the convulsing rats disclosed differences in the DG uptake pattern of the substantia nigra across the 3 age groups. Increases in the DG uptake were present in the two older age groups but not in the pups. Since recent data have implicated the substantia nigra as a crucial site in a seizure modifying circuitry in adult animals, our results suggest that the lack of substantia nigra involvement in the pups may account for the early generalization and the increased severity of seizures in this age group.

Effect of Ketogenic Diet on Convulsive Threshold and Brain Monoamine Levels in Young Mice

Effect of Ketogenic Diet on Convulsive Threshold and Brain Monoamine Levels in Young Mice

Alteration of convulsive threshold and conditioned avoidance response in mice fed diets containing contraceptive steroids.

Female CD1 mice given the contraceptive steroids mestranol and norethynodrel (1:10) in the diet (0.0033%) for 4 months had a growth reduction of 20% when compared with mice fed a normal diet, and had lower convulsive thresholds when tested with the vitamin B6 antagonists 2,4-dimethyl-5-methyl-hydroxypyrimidine and thiosemicarbazide. In conditioned avoidance response (CAR) tests, mice fed the steroid-containing diets showed a decreased acquisition performance during all six sessions; however, mice fed the same diet supplemented with vitamin B6 (0.04%) performed as well during the last three sessions of the CAR tests as mice fed the normal diet.

Tonic convulsive thresholds and responses during the postnatal development of rats administered 6-hydroxydopamine or 5,7-dihydroxytryptamine within three days following birth

The maturation of the electroshock tonic convulsive pattern and threshold was investigated in rats between the ages of 4 and 30 days following intracisternal injections of 6-hydroxydopamine (6-OHDA) on postnatal days 1 and 2; or 5,7-dihydroxytryptamine (5,7-DHT) after desipramine on postnatal day 3. In 6-OHDA treated rats decreases in brain norepinephrine (mean values of 55% of control) and dopamine (mean values of 17% of control) were associated with a large reduction in the convulsive threshold and intensification of the pattern on postnatal day 4. Whereas the reduction in catecholamine concentrations and the intensification of the pattern were still evident on postnatal day 30, the last day of testing, the threshold effect was not evident by postnatal day 15. Although 5,7-DHT reduced brain serotonin concentrations (mean values of 59% of control) as early as postnatal day 4, the pattern was not intensified until postnatal day 8, and the threshold was not reduced until postnatal day 21. These effects were still evident on postnatal day 30. The results demonstrate a sequential maturation of monoaminergic regulation in seizure susceptibility and severity, with an apparent transition from catecholaminergic to serotonergic regulation of the tonic threshold during the third postnatal week.

Effects of a TRH analog (DN-1417) and TRH-T on the electroconvulsive threshold.

Cannulas were chronically implanted in the ventriculus lateralis of rats. The anticonvulsant effects of DN-1417 (γ-butyrolactone-γ-carbonyl-histidyl-prolinamide citrate) and TRH-T (pyroglutamyl-histidyl-prolinamide tartrate) were analyzed by observing the changes in convulsive threshold to electrical stimulation. Both DN-1417 and TRH-T had no significant effect on the electroconvulsive threshold. DN-1417 had an anticonvulsant effcet in animals pretreated with α-methylparatyrosine (α-MT). When rats were pretreated with FLA-63, a dopamine-β-hydroxylase inhibitor, the convulsive threshold was only slightly different from the control threshold, therefore, the decrease in the convulsive threshold by α-MT must be due primarily to a decrease in dopamine (DA) content. Changes in the DA content of the striatum also suggested that the anticonvulsant effect of DN-1417 was due to its DA releasing action. Furthermore, the anticonvulsant effect of DN-1417 seemed to have no relationship to the inhibitory activity of GABA.

Circadian rhythms of folate and vitamin B 12 concentration in relation to convulsive thresholds of mice

Circadian rhythms of folate and vitamin B 12 concentrations in the liver, brain and blood of Swiss mice have been determined. The relation of the changes in vitamin concentration to circadian rhythms in locomotor activity, drinking activity and convulsive thresholds (maximal electroshock seizure threshold) have been determined also. Both free folic acid (FFA) and total folic acid (TFA) of liver and blood showed minimum values at 21.00–24.00 h and maximum values at 06.00–09.00 h. Liver TFA declined at a steady rate from the peak value at 09.00 h whereas liver FFA and plasma folate maintained constant values from 09.00–18.00 h then declined rapidly. Brain folate (TFA and FFA) showed no rhythm. The concentrations of vitamin B 12 in plasma, liver and brain showed only minor fluctuations. Locomotor and drinking activities showed very similar rhythms with a sustained period of high activity between 12.00–21.00 h followed by a much shorter second period of high activity (23.00–03.00 h). Convulsive threshold declined during the first period of increased locomotor and drinking activities reaching a minimum value at 21.00 h thus just preceding the nadir in folate concentrations in liver and blood.

Changes in the convulsive threshold in the developing rat following chronic administration of pentylenetetrazol.

The acute and chronic effects of pentylentetrazol (PTZ) on convulsive behavior in the developing rat pup were investigated. Acute treatment at 10 or 15 days of age with 50 or 80 mg/kg evoked clonic or tonic-clonic convulsions from all rats. However, daily administration of equivalent dose levels from 5 to 16 days of age was associated with a marked reduction in the incidence of these convulsions. Alternate day treatment from 5 to 16 days of age with 80 mg/kg or an ascending series of dose levels (10 mg/kg/day increments) was not accompanied by a reduction in convulsive behavior. The present results indicate that treatment of infant rats with PTZ is followed by a 24-48 h increase in convulsive threshold. This phenomenon may be associated with a developmental process since daily treatment past 15 days of age was characterized by a gradual reappearance of convulsive behavior.

Anticonvulsant actions of the putative gamma-aminobutyric acid (GABA)-mimetic, ethylenediamine.

1 Ethylenediamine, 31.6-1000 mg/kg intraperitoneally, inhibited the convulsive effects of pentylenetetrazol, 100 mg/kg (i.p.) in mice. 2 Ethylenediamine, 100-1000 mg/kg (i.p.) increased the convulsion threshold to the intravenous infusion of three convulsants in the order pentylenetetrazol greater than bicuculline greater than strychnine. 3 The benzodiazepine antagonist R0 15-1788, 10 mg/kg (i.p.), significantly inhibited the anticonvulsant action of diazepam, 50 micrograms/kg, but not ethylenediamine, 1000 mg/kg. 4 These results clearly indicate that ethylenediamine has anticonvulsant properties and are consistent with the hypothesis that ethylenediamine is a gamma-aminobutyric acid (GABA)-mimetic.

Effects of high‐intensity microwave pulse exposure of rat brain

Previous studies have indicated that auditory responses could be evoked in the head of animals exposed to 500‐μs‐wide or less microwave pulses of relatively small absorbed energies (5–180 mJ/kg). These studies were extended using an exposure system capable of locally exposing the head and especially the brain of the animal to a single 915‐MHz pulsed magnetic field with sufficient intensity to produce a specific absorption rate level as high as 4×105 W/kg for any pulse width. When the animal was exposed to various pulse widths (1μs to 360 ms) and power levels (2–10 kW), the animal displayed no reaction other than that due to the hearing effect until the peak absorbed energy density in the brain exceeded 28 kJ/kg, or an absorbed energy in the head of 680 J, regardless of peak power or pulse width. Thermographic and thermocouple measurements indicated a maximum temperature rise of 8°C or final maximum brain temperature of 46° −46.5°C at the reaction level. The reaction consisted of petit or grand mal seizures lasting for 1 min after exposure, followed by a 4‐ to 5‐min unconscious state during which normal reflexes were displayed. There was a decrease in heartbeat rate in the exposed unanesthetized animals. After the period of unconsciousness the rats recovered without apparent effect from the exposure. Measurements indicated that the brain temperature returned to baseline level within 5 min after exposure and the animals began moving when the brain temperature returned to within 1°C of their normal values. These results would indicate that the thresholds for convulsions induced by short exposures of the brain to high energy pulses are dependent only on the deposited energy and temperature rise. Histological examinations of some of the animal brains indicated some demyelination of neurons 1 day after exposure and some microfocal glial nodules in the brain 1 month after exposure.

Electro-convulsive therapy with minimum hazard.

The inter-electrode resistance during ECT is shown to be very variable, a finding which invalidates the measurement of shocks in joules. With square wave pulses of selected current value the threshold for convulsion may be below 100 milliamperes or above 2,000 milliamperes. It is advisable to measure the current value during millisecond pulses with relatively long intervals between.

Synergism of hyperoxia and high helium pressures in the causation of convulsions.

Hyperoxia beyond 1.8 ATA results in a striking reduction of high-pressure neurological syndrome (HPNS) type I convulsion threshold pressures but is without measurable effect on type II convulsions. The synergism is partially or completely reversed by increasing alveolar or tissue CO2 levels. High total pressures (PI) result in striking reductions in the duration of hyperoxic exposure preceding seizure onset (tc). The interaction of hyperoxia and high pressure gives rise to three zones on the PO2-Pt plane. In zone I, Pt less than 30 ATA, the duration of hyperoxia prior to convulsion onset is given by the equation PO2 -- PO2 lim = K/(tc -- tc lim), where PO2 lim and tc lim both decrease with increasing total pressure. Zone II, Pt = 30-50 ATA and PO2 1.8-2.3 ATA, is characterized by a sharp drop in tc, as Pt is increased beyond 30 ATA, to a value near 15 min that is constant within the PO2 limits given. In zone III, Pt greater than 50 ATA and PO2 greater than 0.2 ATA, tc is of the order of 2 min, and the seizures are essentially HPNS seizures only slightly modified by hyperoxia. The data are interpreted as suggesting that zone I represents hyperoxic seizures facilitated by high pressures, whereas zone II represents HPNS type I seizures facilitated by hyperoxia.

Drugs that increase gamma-aminobutyric acid transmission protect against the high pressure neurological syndrome.

1 The effects on the high pressure neurological syndrome (HPNS) of drugs which facilitate gamma-aminobutyric acid (GABA) transmission were investigated. Threshold pressures for the onset of the behavioural signs of the HPNS in mice--tremors and convulsions were established. 2 Flurazepam hydrochloride 20 and 10 mg/kg and sodium valproate 800 and 400 mg/kg substantially raised the threshold pressures for both tremor and convulsions. 3 Amino-oxyacetic acid 35 and 25 mg/kg and diaminobutyric acid 600 mg/kg also significantly increased the thresholds. Muscimol 1 mg/kg (and 150 ng i.c.v.) was ineffective at non-toxic doses. 4 These effects paralleled the drugs' ability to raise the convulsion threshold to intravenous infusion of bicuculline in mice. 5 These results demonstrate that drugs with actions more selective than those of the general anaesthetics are effective against the HPNS. It is also possible that there is a GABAergic component to the effects of general anaesthetics on the HPNS.

Specific action of tranylcypromine to precipitate barbital withdrawal convulsions.

This research was designed to determine whether the convulsion-eliciting action of tranylcypromine (TCP) during bartibal (B) withdrawal was specific to physical dependence on B, and to compare the findings with the action of pentetrazol (PTZ). Challenge with 15-20 mg/kg IP TCP at 48 or B withdrawal resulted in the elicitation of clonic-tonic convulsion (CTC) in all rats (n = 6) within 10 min. Another challenge with 5-20 mg/kg TCP led to the dose-related precipitation and intensification of CTC. The CTC-inducing action of TCP was relatively reduced as the B withdrawal signs were gradually mitigated. In other words, when challenge with the drug was made at 72h of B withdrawal, the time of CTC onset was prolonged, and the incidence was reduced to 50% in parallel with abolition of the other withdrawal signs. A challenge at 120 h of B withdrawal when the vital signs had almost recovered to prewithdrawal level failed to induce even the prodromal signs of convulsion. In all rats exhibiting only mild to moderate withdrawal signs (such as hyperirritability, hyper-reflexia, anorexia, weight loss), 40 mg/kg TCP was required to induce CTC during B withdrawal, which was twice the dose required in severely dependent rats. Other monoamine oxidase inhibitors, i.e., pargyline, iproniazid, and clorgyline, elicited no CTC during B withdrawal. Methamphetamine was without effect on B withdrawal convulsions. From these findings, the convulsive threshold for TCP during B withdrawal proved well correlated to the grade of B-dependence and the duration of B-withdrawal signs.

Long-term inhibition of kindled seizures by brain stimulation

It was concluded from previous studies that prior stimulation produced a long-lasting inhibition of kindled seizures only when a series of convulsions were evoked. The present study describes a brain stimulation procedure capable of producing a long-lasting inhibition of kindled convulsions without evoking prior convulsions of EEG afterdischarge. Electrodes were implanted in the amygdala of rats, which were then kindled to a criterion of five successive tonic-clonic convulsions. After kindling, the animals were exposed to a regimen of intermittent amygdala stimulation, which was gradually increased in intensity in small incremental steps from a point just below the convulsion threshold to an intensity above the original kindling current. Using this procedure, it proved possible to administer high stimulation intensities without evoking any behavioral convulsions or EEG afterdischarges. Subsequent to this inhibitory procedure, amygdala stimulation did not evoke convulsions or EEG seizures for as long as 7 days. Additional studies tested the relative effectiveness of different stimulation rggimens and parameters for producing long-lasting inhibition of kindled seizures. The magnitude of the incremental intensity steps, the interstimulus interval, and the intensity of stimulation all proved to be relevent. We concluded that long-lasting inhibition of kindled seizures could be produced by prior stimulation that did not evoke seizures.

Role of nasal air flow in convulsions induced by lidocaine in the rat

Prevention of nasal air flow by temporary occlusion of the nares significantly lowered the convulsive threshold to lidocaine and pentylenetetrazol in the rat. This result indicates that olfactory stimulation is not a contributing factor in convulsions induced by local anesthetic agents such as lidocaine.

Age-dependent reduction in maximum electroshock convulsive threshold associated with decreased concentrations of brain monoamines

This study investigated modification of the tonic convulsive threshold to maximum electroshock in 15- and 30 day old rats treated with drugs which reduce steady-state concentrations of monoamines. On postnatal day 15, reduction of central catecholamine concentrations by 6-hydroxydopamine or of central serotonin concentrations by 5,7-dihydroxytryptamine or p-chloroamphetamine did not alter the tonic convulsive threshold. However, simultaneous depletion of catecholamines and serotonin by tetrabenazine was associated with a significant decrease in the tonic threshold. This effect could be reversed partially by simultaneous administration of the catecholamine and serotonin precursors, L-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively. On postnatal day 30, reduction of brain serotonin concentration, but not catecholamine concentrations, was associated with a significant decrease of the tonic convulsive threshold. In a previous study, in which 7–8 day old rats were used, a tetrabenazine-induced decrease in the tonic convulsive threshold was prevented by L-dihydroxyphenylalanine bu t not 5-hydroxytryptophan. Furthermore, intracisternal 6-hydroxydopamine, but not 5,7-dihydroxyhyptamine, decreased the threshold on postnatal day 8. Therefore, the results of the present study involving 15- and 30 day old rats, together with the earlier findings in 7–8 day old rats, [28] suggest an apparent developmental transition from catecholaminergic to serotonergic dominance in regulation of the tonic convulsive threshold during the first postnatal month.

Potentiation of metrazol convulsions in chickens after neonatal injections of cycloheximide or glutamate

Chickens which received forebrain injections of cycloheximide or glutamate when newly hatched were found to be more susceptible to metrazol-induced convulsions at 6–8 weeks of age. It is possible that these changes in convulsive threshold are related to alterations in dopaminergic transmitter systems found in the birds.

Alteration of convulsive threshold and sensitivity to CNS acting drugs in sedative-hypnotics-experienced rat offspring.

The present study was made to investigate the developmental toxicity of ethanol and several sedative-hypnotics (barbital, diazepam, phenobarbital) administered to rat pups via dams for 18 days (day 3-21 after parturition) from the relatively early postnatal stage in terms of changes in the threshold for pentetrazol (PTZ)-induced convulsion, tolerance to, and physical dependence on barbital (B). In the pups of all dosed groups, the convulsive threshold for PTZ is reduced significantly compared with that in the naive group. The sleeping time with B in phenobarbital-exposed offspring was also reduced significantly compared with that in the naive pups. No difference was however, noted in the B concentration of the brain or plasma upon awaking between these groups of pups, which proved that the phenobarbital-exposed pups had obviously acquired a functional tolerance to B. B-dependence formation and the ensuring weight loss and appearance of withdrawal signs, especially clonic-tonic convulsion, were made intense in the phenobarbital-experienced pups. From these results, it may be concluded that exposure to sedative-hypnotics from the early CNS developing stage makes a lowered state of convulsive threshold for PTZ, and therefore, tends to enhance B-withdrawal convulsion. These phenomena were discussed from the viewpoint of monoamine metabolism in the brain.

ALTERATION OF CONVULSIVE THRESHOLD AND SENSITIVITY TO CNS ACTING DRUGS IN SEDATIVE-HYPNOTICS-EXPERIENCED RAT OFFSPRING

The present study was made to investigate the developmental toxicity of ethanol and several sedative-hypnotics (barbital, diazepam, phenobarbital) administered to rat pups via dams for 18 days (day 3-21 after parturition) from the relatively early postnatal stage in terms of changes in the threshold for pentetrazol (PTZ)-induced convulsion, tolerance to. and physical dependence on barbital (B). In the pups of all dosed groups, the convulsive threshold for PTZ is reduced significantly compared with that in the naive group. The sleeping time with B in phenobarbital-exposed offspring was also reduced significantly compared with that in the naive pups. No difference was however, noted in the B concentration of the brain or plasma upon awaking between these groups of pups, which proved that the phenobarbital-exposed pups had obviously acquired a functional tolerance to B. B-dependence formation and the ensuing weight loss and appearance of withdrawal signs, especially clonic-tonic convulsion, were made intense in the phenobarbital-experienced pups. From these results, it may be concluded that exposure to sedative-hypnotics from the early GNS developing stage makes a lowered state of convulsive threshold for PTZ, and therefore, tends to enhance B-withdrawal convulsion. These phenomena were discussed from the viewpoint of monoamine metabolism in the brain.

Individualisation des epilepsies dites «benignes ou «fonctionnelles aux differents ages de la vie. Appreciation des variations correspondantes de la predisposition epileptique a ces ages

The different types of epilepsy encountered during the various phases of life are presented and the distinction is made between benign and, essentially if not exclusively, functional epilepsy related to a genetically-transmitted predisposition to epilepsy: (1) the primary generalized epilepsies and (2) the benign partial epilepsies with functional foci. In the case of primary generalized epilepsy, seizures are the result of a discharge, generalized from the onset, of the entire cortex in individuals genetically predisposed to epilepsy. The seizures present (1) in older children, adolescents and young adults, the well-known characteristics of Petit Mal and/or Grand Mal; (2) in neonates, infants and young children, a different type of generalized (or hemigeneralized) seizures, the semeiology of which remains unclear. In the case of benign partial epilepsy, the seizures result from an epileptic discharge in a cortical area having a low convulsant threshold in patients genetically predisposed to epilepsy. The semeiology of the seizures varies as a function of the patient's age and the site of the epileptic focus: -in neonates: benign partial epilepsy wih an erratic EEG focus, e.g. 'Fifth day seizures'; -in infants: 'cryptogenic' benign partial epilepsy, which remains poorly defined; -in children: (a) benign partial epilepsy with nocturnal motor seizures and a central EEG focus; (b) benign partial epilepsy with affective seizures and a temporal focus; (c) benign partial epilepsy with visual seizures (often coupled with signs of basilar migraine) and an occipital focus; -in adolescents: benign partial motor epilepsy (often versive) often without an interictal EEG focus or with generalized spike-waves; benign partial epilepsies do not occur after adolescence.