Seizure Susceptibility In Rats Research Articles

Subcellular distribution of neuroactive amino acids in brains of genetically epileptic rats.

The subcellular distribution of amino acids was compared in brains of genetically seizure-susceptible (SS) and genetically seizure-resistant (SR) rats. The total taurine content (mumol/brain) in the P2B, or synaptosomal, fraction in SS rats was only 37% of that of SR rats. Glutamate, glutamine, glycine, alanine, and gamma-aminobutyric acid (GABA) contents were unaltered. No alterations in total content were found in other subcellular fractions for the amino acids studied. SS animals that had never been stimulated to audiogenic seizure had decreased concentrations of taurine (nmol/mg protein) in the P2, P2B, and P2C fractions as compared with SR animals. These fractions contain crude synaptosomes, enriched synaptosomes, and enriched mitochondria, respectively. Phosphoethanolamine concentrations were also decreased in the P2B fractions, but concentrations of other amino acids were unaltered, as compared with SR animals. Twenty-four hours after the intracerebroventricular injection of taurine (6 mumol) in SS animals that had never been convulsed, taurine concentrations were significantly increased in whole brain homogenate and P2 and P2B fractions as compared with SS animals not given taurine. This treatment left unaltered the concentrations of glutamate, glutamine, GABA, and glycine in brain homogenate and P2 fraction. Because decreases in taurine concentration were seen in animals that had not been convulsed, these alterations are intrinsic to the SS strain and are not a consequence of convulsive activity. In view of the antiepileptic action of taurine, and the fact that an impairment of taurine transport in the brain of SS rats had previously been demonstrated, we suggest that a defect in the biochemistry of taurine is partially responsible for the seizure susceptibility of the SS rat.

The effect of changes in sound pressure level and frequency on the seizure response of audiogenic seizure susceptible rats

An apparatus for pure tone stimulation of audiogenic seizure (AGS)-susceptible rats is described, and the effect of change in sound pressure level and frequency on AGS response in Uaz:AGS (SD) rats is shown. By use of pure tone stimulation, the prevalence of AGS response in rats of this strain, which have been bred for seizure-susceptibility, is 77%. With increasing frequency, the intensity-response curves show a shift to lower sound pressure levels, the ED 50 for 20 kHz (83.8 dB) being significantly lower than the ED 50 for 5 (110.5 dB) and 10 kHz (97.5 dB). Repeated exposure to seizure-inducing sound at weekly intervals leads to more severe seizures in individual rats. This should be taken into consideration as one possible confounding factor when using this method for assaying the efficacy of anticonvulsant drugs.

Cortical spike wave discharges during audiogenic convulsions in rats

Audiogenic seizure-susceptible rats show high-amplitude spikes and waves in the electrocorticogram during the tonic phase of a maximal audiogenic convulsion. This observation establishes the validity of this seizure type as an animal model for human generalized epilepsy.

Seizure-susceptibility and decreased taurine transport in the genetically epileptic rat

P 2 fractions from brains of genetically seizure-susceptible (SS) rats as compared to seizure-resistant (SR) rats show decreased high affinity uptake of taurine. Uptakes of GABA and glutamate into P 2 fractions did not differ between the substrains. In neonatal SS rats that had never had a seizure, the uptake of taurine is decreased both into the whole brain in vivo and into P 2 fraction in vitro, as compared to age-matched SR rats. This indicates that decreased uptake is not a consequence of seizure activity per se. In non-seizure susceptible progeny of SS rats, the uptake of taurine into P 2 fraction did not differ significantly from that of SR rats. In kidney cortex slices from SS rats, taurine uptake is slightly greater than in slices from SR rats. We propose that the decreased taurine transport in the P 2 fraction of the brains of SS rats may reflect a defect in transport in vivo that contributes to seizure-susceptibility.

The transport, biosynthesis and biochemical actions of taurine in a genetic epilepsy

We have investigated the transport, biosynthesis and turnover of taurine in genetically seizure-susceptible (SS) and seizure-resistant (SR) rats. In SS rats, the rate of taurine uptake into the brain was half the rate in SR rats. As no difference was found in biosynthesis of taurine, these results imply a slower turnover of taurine in SS brain. The effect of taurine on the decarboxylation of glutamate in brain homogenates was determined. In homogenates of SR brains, taurine had no effect but in SS preparations taurine increased the rate of decarboxylation by 20%. Increased decarboxylation of glutamate may be one basis for the prolonged anticonvulsant action of taurine in the SS rat.

Effects of withdrawal from long-term barbital treatment on open-field behaviour and seizure susceptibility of rats

Rats withdrawn from long-term barbital treatment were tested both for theiractivity in an open-field and for their sensitivity to convulsant stimuli. Barbital withdrawal induced a significant increase on locomotion and rearing frequency. Drug removal also made the rats more sensitive to convulsion elicited by sound and maximal electroschok. A positive correlation was found between locomotion plus rearing frequency and audiogenic-induced seizures 3, 4 and 5 days after barbital withdrawal. The results show that exploratory behaviour evaluated through the open-field method can be used as a reliable method to show barbital withdrawal in rats. Taken together, the results suggest that long-term barbital treatment might develop a supersensitivity state, in noradrenergic neurons in the central nervous system.

The role of the locus coeruleus in regulation of seizure susceptibility in rats.

When studying the role of the locus coeruleus (LC) in the regulation of seizure susceptibility in rats, we found that bilateral LC lesion significantly lowered the electroshock seizure threshold for the tonic extension of forelegs. The pattern of maximal electroshock seizure was not affected by LC lesion, although the recovery time was slightly prolonged. In the pentylenetetrazol (PTZ) seizure threshold test, LC lesion significantly elevated the twitch threshold, but did not affect the threshold for the generalized clonic seizure or clonic convulsion. Incidence of the tonic extension in the PTZ seizure test tended toward an increase with LC lesion. Biochemical determinations revealed that LC lesion significantly decreased the norepinephrine contents in various brain regions as well as the 5-hydroxytryptamine contents of some brain regions, but not the 5-hydroxyindoleacetic acid contents. These results suggest that while the LC is involved in the regulation of seizure susceptibility, the involvement differs with various types of seizures.

THE ROLE OF THE LOCUS COERULEUS IN REGULATION OF SEIZURE SUSCEPTIBILITY IN RATS

When studying the role of the locus coeruleus (LC) in the regulation of seizure susceptibility in rats, we found that bilateral LC lesion significantly lowered the electroshock seizure threshold for the tonic extension of forelegs. The pattern of maximal electroshock seizure was not affected by LC lesion, although the recovery time was slightly prolonged. In the pentylenetetrazol (PTZ) seizure threshold test, LC lesion significantly elevated the twitch threshold, but did not affect the threshold for the generalized clonic seizure or clonic convulsion. Incidence of the tonic extension in the PTZ seizure test tended toward an increase with LC lesion. Biochemical determinations revealed that LC lesion significantly decreased the norepinephrine contents in various brain regions as well as the 5-hydroxytryptamine contents of some brain regions, but not the 5-hydroxy-indoleacetic acid contents. These results suggest that while the LC is involved in the regulation of seizure susceptibility, the involvement differs with various types of seizures.

Acute and chronic antiepileptic drug effects in audiogenic seizure-susceptible rats

In audiogenic seizure (AGS)-susceptible rats, the acute dose-response effects of antiepileptic drugs administered intraperitoneally in preventing AGS and in causing rotorod neurotoxicity (ROT) were determined. Rank-order efficacies of drugs based on their protective indexes [ratio of median neurotoxic doses (ROT TD 50) to median effective doses (AGS ED 50)] were primidone (74.6), phenacemide (13.5), clonazepam (10.8), carbamazepine (5.9), phenobarbital (3.8), phenytoin (3.7), trimethadione (3.1), valproic acid (2.3), and ethosuximide (2.0). Further, the anti-AGS effects and plasma concentrations of phenobarbital were ascertained after doses of phenobarbital (45 mg/kg, acute, i.p., ED 97) given every 12 h for 25 days. AGS tests and/or plasma analyses were carried out for 27 days at 2, 12, 14, 22, and/or 40 h after phenobarbital injection. Efficacy against AGS was directly related to postinjection times of testing and corresponding plasma concentrations, i.e., 100% protection of AGS at 2 and 12 h, 70% at 14 h, and 0% at 22 and 40 h; minimal plasma concentrations of 10 to 15 mg% appeared maximally effective in preventing AGS during 25 days. However, tolerance to phenobarbital-induced sedation and ataxia did occur. Also, a linear decline of plasma phenobarbital during the 40 postinjection h indicated first-order elimination kinetics and a half-life time of 12 h. These data indicate that the AGS test coupled with ROT test is reliable for identifying and ranking prototype antiepileptic drugs. Further, tolerance to AGS does not occur with phenobarbital when optimum and steady-state plasma concentrations of phenobarbital are maintained. These findings suggest that the AGS-susceptible rat model may offer a useful approach to the screening and development of pharmacotherapeutic agents for the treatment of the epilepsies.

Repeated electroconvulsive shock does not increase the susceptibility of rats to a cage convulsant (Isopropylbicyclophosphate)

Intravenous infusion of isopropylbicyclophosphate (IPTBO), a cage convulsant, produced a seizure which was qualitatively very similar to that seen after picrotoxin administration, but with a shorter latency. Pretreatment of rats with either a single electroconvulsive shock (ECS) or a single ECS daily tor 10 days did not alter the dose of IPTBO necessary to elicit a seizure 24 h after the final ECS. This data together with other previously published work argues against repeated ECS altering seizure susceptibility in rats.

Audiogenic seizures and cochlear damage in rats after perinatal antithyroid treatment.

The feeding of goitrogens during pregnancy and lactation causes the offspring of rats to be partially deaf and persistently sensitive to audiogenic seizures. The most potent goitrogen, propylthiouracil, caused severe dysfunction and disorganization of the organ of Corti. Adult seizure-susceptible rats showed increased sensitivity to audiogenic seizures when they were fed propylthiouracil.

Are amino acid patterns necessarily abnormal in epileptic brains? studies on the genetically seizure-susceptible rat

Free amino acid concentrations have been compared in brain regions from genetically seizure-susceptible and seizure-resistant rats. No significant differences were found in either the inferior colliculus, a region of low electroshock threshold in seizure-susceptible animals, or in the ?, a region of high electroshock threshold. No changes were found in the ratios between glutamate, glutamaine, taurine, GABA or glycine. These findings invalidate the universality of the hypothesis linking seizure susceptibility to imbalances in glutamate: glutamine ratio. It has been proposed that the anticonvulsant action of taurine is due to rectification of abnormal glutamate levels. Taurine is a potent anticonvulsant in the seizure-susceptible rat, yet no imbalances of glutamate content are present.

Effect of intracisternal 6-hydroxydopamine on seizure susceptibility in rats

Rats with 60–70% deficits in brain catecholamines produced by the intracisternal injection of 6-hydroxydopamine were examined by 3 tests of seizure susceptibility. In all procedures (minimal and maximal electroshock and flurothyl convulsions) evidence for increased sensitivity to seizures was obtained. All the animals displayed normal rectal temperature at the times of seizure testing and normal blood chemistry at approximately the time of the third seizure test. These observations strengthen the widely held hypothesis that brain catecholaminergic neurons play a fundamental role in governing sensitivity to convulsions.

Influence of treatment duration on audiogenic seizure susceptibility during barbiturate withdrawal in rats.

Barbiturate withdrawal seizure susceptibility in rats increased with increasing duration of treatment during a 15-day treatment period in which the animals were given an i.p. dose of sodium barbital every 12 h. This method of producing dependence has clear advantages over previously described methods.

The Prolonged Anticonvulsant Action of Taurine on Genetically Determined Seizure-Susceptibility

SUMMARY:A prolonged anticonvulsant action of taurine has been shown in a strain of seizure susceptible rats. The audiogenic rat (AS) has lower intracerebral electroshock thresholds in three auditory nuclei; the ventral cochlear, the inferior colliculi and the medial geniculate, and in one nonauditory structure; the reticular formation, than a strain of nonaudiogenic rats (NAS). Furthermore, the AS animals routinely display maximal (tonic-clonic) convulsion, regardless of brain structure stimulated, whereas NAS subjects respond with minimal (clonic) convulsions. Within three minutes of intraventricular injection of 8 μ moles, taurine reduces the susceptibility of AS rats to intracerebral electroshock seizures along with attenuation of the severity of the convulsion. The initial elevation in intracerebral electroshock threshold returns to pretreatment value at 24 hours, only to rise again at 48 hours and to remain elevated through day six after injection. In contrast, the severity of convulsions remains attenuated through 24 hours, after which it returns to pre-injection level. By comparison, NAS animals injected intracerebroventricularly in an identical fashion to the AS rats showed no changes in either seizure threshold or severity of convulsion. The direct injection of 200n-moles of taurine in the inferior colliculi of AS rats produced a slow developing, but prolonged, elevation of intracerebral electroshock threshold of this auditory nuclei. However, at no time after the intracerebral injection of taurine was convulsive severity changed. Injection of taurine into the inferior colliculi of NAS subjects did not change either susceptibility or severity of intracerebral electroshock seizures. The data indicate that taurine produces an anticonvulsant effect which is slow in onset, potent, selective and prolonged.

Effect of magnesium deficiency on nonspecific excitability level (NEL) and audiogenic seizure susceptibility

Magnesium deficiency in weanling rats caused an increase in NEL and in audiogenic seizure susceptibility. These behavioral effects were apparent after eight days of magnesium restriction and could be reversed by dietary rehabilitation. Serum magnesium declined rapidly from1.87 ± 0.10mEq/Lto0.91 ± 0.24mEq/L in two days. Cerebrospinal fluid (CSF) magnesium decreased gradually from 1.86 mEq/L, becoming significantly lower (1.44 ± 0.23mEq/L) after eight days. When deficient rats were injected IP with MgCl 2, raising the serum magnesium concentration to 6.6 mEq/L, NEL decreased to normal while audiogenic seizure susceptibility remained. Both NEL and audiogenic seizure susceptibility in rats reflect central nervous system magnesium concentration, except when serum magnesium concentration is very high. Very high serum magnesium concentration lowers NEL but does not reduce audiogenic seizure susceptibility if CSF magnesium is low.

Circadian alteration of audiogenic seizure susceptibility in rats

Genetically determined audiogenic seizure susceptibility in Wistar albino rats showed distinct rhythmicity with its increase and decrease during night and day, respectively. This rhythmicity is apparently regulated by light since its trend can be readily reversed by artificially reversing the illumination pattern of day-night schedule in their colony. This is best observed in rats which are arbitrarily classified as nonsensitive with no response to six day-time audiogenic stimulations on alternate days.

Susceptibility to audiogenic seizure induced by thiosemicarbazide

Rats, cats, and monkeys were subjected to audiogenic stimuli after the administration of thiosemicarbazide (TSC). The treated rats responded to audiogenic stimulation with episodic running behavior (ERB) with or without convulsion (C), the most effective dosage being 4.4 mg/kg. In rats, the pattern of audiogenic response in genetically sensitive rats and TSC-treated nonsensitive rats was indistinguishable. Treatment of audiogenic-sensitive rats with TSC produced some accentuation of audiogenic response. Cats responded to audiogenic stimulation with ERB, ERB + C, C + ERB, or C alone. In addition, entirely independent and spontaneous convulsion was observed. The threshold dosage was 7.0 mg/kg. Monkeys responded to audiogenic stimulation with C, motor excitement followed by C, or C followed by repetitive vocalization or motor excitement. Monkeys also showed independent and spontaneous C. In cats and monkeys, unlike methionine sulfoximine-induced episodic behavior, spontaneous C and audiogenic response were not mutually exclusive. Although some electrographic evidence of preferential involvement of temporal lobe structures was obtained, no discernible seizure discharge was observed in any brain structures explored during ERB or restlessness induced by audiogenic stimulation. In spite of some interspecies response variation it was conclusively shown that TSC induces transient audiogenic seizure susceptibility in rats, cats, and monkeys.

Effects of levels of audiogenic-seizure susceptibility on endocrine function of rats

The present study searched for relationships and correlations between the respective level of individual audiogenic-seizure susceptibility patterns and metabolic and endocrine differences in seizure-susceptible vs. resistant animals. Immature, female Wistar rats were subjected to high intensity alarm bell stress (115–120) db and scored for variations in intensity and frequency of behavioral reactions (i.e., wild-running seizures and convulsions, for 5 min, at 4 equally spaced occasions during a 2-week testing period. Recording of fecal pellet counts, urine excretion volumes, O 2 consumption and subsequent organ weight differences noted after autopsy at the end of a following 2-week period, revealed significant increases in fecal and urinary elimination rates of the seizure-susceptible rats; significant increases in the relative adrenal weights were, likewise, accompanied by corresponding increases in adrenal ascorbic acid content per gland and significant decreases in the thymus weights of the seizure-susceptible rats. The greatest percent differences and degree of changes were noted in the most highly susceptible rats which suffered wild-running seizures and convulsive attacks at all 4 testing trials. The addition and inclusion of less susceptible animals in the group analyses consistently caused a diminution in the level of differences between the most highly susceptible group and the resistant-control group. The range and differences in adrenal, thymus and ascorbic acid values of the most susceptible rats (Group 1) vs. total susceptible (Group 1, 2 and 3) vs. the seizure-resistant control group suggest a direct relationship of adrenal function to the level of seizure susceptibility. The difference in fecal pellet counts and urine excretion values, similarly afforded evidence of alteration in food metabolism and excretory reflexes of the susceptible animals.

The susceptibility to auditory stimuli of animals treated with methionine sulfoximine

Cats and rats were subjected to repeated sounds made by rattling a key chain or ringing an electric doorbell following administration of methionine sulfoximine. The treated cats responded to these sounds with episodic running behavior, the most effective dosage being 7.5 mg/kg. The effects were entirely reversible, beginning at 15–27 hours after administration and lasting for 36–69 hours. Behavioral responses elicited by auditory stimulation were either a fully-developed or an abortive form of episodic running; a minor percentage had associated convulsions of type C-1. Those cats which developed independent convulsions of type C-2 prior to auditory stimulation completely failed to show susceptibility. Methionine sulfoximine produced susceptibility in nonsusceptible rats starting at about the sixth hour and lasting for about 10 hours. In doses of 200 and 300 mg/kg the drug was most effective in producing completely reversible susceptibility with either episodic running alone or followed by generalized convulsions of type C-1. All the convulsive seizures observed in rats following auditory stimulation were secondary to the episodic running behavior. In a dosage of 200 mg/kg the drug greatly potentiated the susceptibility of genetically determined audiogenic seizure susceptible rats without modifying the behavioral manifestations of the seizure response. The episodic behavior in both treated nonsusceptible cats or rats and genetically determined audiogenic sensitive rats is phenomenologically identical with only minor differences in the pattern of the convulsive component between cat and rat. It was conclusively shown that they share the common property of extreme susceptibility to auditory stimulation.