Sleep promoting effect of a putative glial gamma-aminobutyric acid uptake blocker applied in the thalamus of cats.

The uptake of gamma-aminobutyric acid (GABA) by glial cells was decreased when 4,5,6,7,-tetrahydroisoxazolo-(4,5-C)-pyridin-3-ol (THPO) was applied in the thalamus of freely moving cats by in vivo microdialysis. A marked reduction in duration of wakefulness and in number of awakenings was obtained during THPO treatment. THPO did not change the ratio of slow-wave-sleep and paradoxical sleep but only increased the total sleep time. The present data suggest a possible regulatory role of the glial-neuronal interaction in the modification of the sleep-waking cycle.     

The toxic effect of kainic acid on neurotransmitters in nucleus accumbens

Neurotransmitter parameters (GAD, ChAT, high affinity glutamate uptake and QNB binding) in nucleus accumbens showed a dose-dependent sensitivity towards in situ injections of the toxic agent kainic acid. We found that the effect of kainic acid was only to a small part dependent on the main glutamergic input from the subiculum. The study shows that muscarinic receptors in the nucleus accumbens are mostly located on intrinsic neurons.     

Potentiating effect of morphine on seizures induced by kainic acid in rats

Summary The effect of morphine pretreatment on kainic acid-induced seizures in rats was investigated by electroencephalographic recording. Seizure activity was quantified by counting the number of spikes in the EEG of freely-moving rats during 2 min periods at 30 min intervals after the intraperitoneal administration of 8, 10 or 12 mg/kg kainic acid. Pretreatment with morphine (1–10 mg/kg s.c.) 10 min before kainic acid administration significantly increased the number of spikes in the EEG in a dose-dependent manner. The potentiating effect of morphine on kainic acid-induced seizures was reduced considerably, but not abolished completely by pretreatment with naloxone (2–5 mg/kg s.c.). The results indicate that the potentiating action of morphine on kainic acid-induced seizures may be exerted in both a specific, naloxone-reversible manner and a non-specific, naloxone-resistant manner.     

Injections of kainic acid into the raphe dorsal nucleus in freely moving cats: electroencephalographic, behavioral and histopathological consequences.

Results are presented concerning the functional and morphological changes occurring after kainic acid injections into raphe dorsal nucleus in freely moving cats. The effects of kainic acid at two doses, 4 and 12 nmol, on electroencephalographic activity, behavior and cell morphology were examined on the day of injection, and on the 1st, 3rd, 6th, 15th, 30th and 65th day. A well-pronounced dose-dependent effect of kainic acid was established: in 50% of the animals injected with 4 nmol of kainic acid and in 85.7% of the animals injected with 12 nmol electroencephalographic and behavioral seizures appeared. The strength of the seizures in the animals receiving 12 nmol of kainic acid was different--from focal single epileptiform patterns first in raphe dorsal nucleus and then in other brain regions to generalized high-voltage ictal activity and in some animals to epileptic state. In all animals receiving 4 nmol of kainic acid and in 75% of the animals receiving 12 nmol of kainic acid, the electrical activity and behavior returned to normal several hours after or within two days following the kainic acid injection. The histopathological data obtained by light microscopy showed a dose-dependent cytoarchitectural disorganization (mainly chromatolytic changes) not only at the injection site but also in many other brain structures. The present results confirm our previous studies on cats in acute conditions showing enhancement of brain excitability level up to hyperexcitation (seizures) after kainic acid injection into the raphe dorsal nucleus.     

蝎毒抗海人酸诱导大鼠癫痫的作用

目的:研究蝎毒抗海人酸(Kainic acid KA)诱导大鼠癫痫的作用。方法:抗海人酸(10mg/kg)诱发SD大鼠出现急性癫痫发作后,将其分为2组,每天灌胃分别给予生理盐水,蝎毒粗提液(SV 100mg/kg)。10天后再次同剂量KA检测癫痫的敏感性及免疫组化测其检验结果。结果:行为学结果经统计学处理后表明,SV可明显抑制动物癫痫敏感性的形成。免疫组化结果表明, SV可防止海马硬化的形成。     

Comparative behavioural toxicity of domoic acid and kainic acid in neonatal rats

Cumulative behavioural toxicity was measured in groups of male and female rat pups (n=6/sex) at different stages of postnatal development. Dose–response curves (DRCs) for toxicity produced by domoic acid (DOM) were generated using animals on postnatal days (PND) 0, 5, 14, and 22, using a behavioural rating scale. In a subsequent experiment, DRCs for toxicity generated by either DOM or kainic acid were produced in rats at PND 8 and 14 for comparison between the two toxins. DOM was found to be a very potent neurotoxin in newborn rats and the potency of DOM progressively decreased with increasing age (interpolated ED₅₀=0.12, 0.15, 0.30, and 1.06 mg/kg at PND 0, 5, 14, and 22, respectively). In addition, the patterns of behavioural expression were found to differ with age. Comparisons between DOM and kainic acid revealed that DOM was approximately six-fold more potent than kainate at both PND 8 and PND 14 and that both toxins were approximately two-fold less potent in PND 14 rats, compared to PND 8. This implies that the mechanism(s) responsible for reduced potency is/are similar between the two compounds. Consistent with previous reports, however, there were both similarities and differences in the observed patterns of behavioural toxicity produced by the two toxins at both ages.     

Effects of some antiepileptic and proconvulsant drugs on kainic acid-induced limbic epilepsy in cats

The effects of parenteral administration of diazepam (3 mg/kg), DL-C-allylglycine (60–80 mg/kg), and ketamine (20 mg/kg) on kainic acid (KA)-induced limbic seizures were investigated in cats. Single microinjections of KA (1–4 μg) into the amygdaloid complex were followed by local sustained paroxysmal discharges in the limbic system. Seizures consisted of tonic clonic EEG discharges accompanied by orienting reaction to the ipsilateral side of injection and masticatory movements, facial jerks, and aggressive behaviour. Ictal discharges occurred every 5–10 min during the first hours after KA injection and then progressively disappeared within 1 wk. Interictal discharges remained for longer periods, but after 3 or 4 wk they were abolished. Diazepam completely blocked limbic seizures but not high-frequency discharges in the site of injection and the ipsilateral hippocampus. The animals were protected for 30 to 60 min. At the same time, diazepam decreased multiple-unit activity in the pontine reticular formation and the lateral geniculate nucleus and produced a general hypotonia state. DL-C-allylglycine activated KA amygdaloid focus during the remission state and ketamine produced independent epileptiformlike activity which interfered with that produced by KA injection.     

The effect of kainic acid administration into globus pallidus on EEG and behavior of rabbits

Injection of 0,5 microgram of kainic acid into the globus pallidus of rabbits carrying chronically implanted electrodes and cannulas, resulted in an increase of cerebral electrical activity up to appearance of epileptoidal discharges. These effects were prevented by diazepam pretreatment. Behavioral changes produced by kainic acid were biphasic; ipsilateral rotations or postural asymmetries, observed in the early phase, gave way later to contralateral asymmetries. Kainic acid facilitated sniffing episodes, which appeared simultaneously with epileptoidal discharges in the hippocampus. The stimulation of globus pallidus neurons with kainic acid resulted also in electrical activation of the ventral anterior thalamic nucleus. The results indicate that the majority of the neurons of globus pallidus display selective sensitivity to kainic acid and that the globus pallidus is functionally connected with the hippocampus and the ventral anterior thalamic nucleus.     

Microinjection of kainic acid into the rat hippocampus

The effects of unilateral injection of kainic acid into the rate hippocampus have been examined in terms of morphologic, neurochemical and behavioral sequelae. Infusion of 10 nmoles if kainate causes a rapid and complete degeneration of neuronal perikarya in the entire hippocampal formation followed by gliosis and atrophy of the region. This unilateral neuronal loss is accompanied by a 50% decrease in the specific activity of the biochemical markers for GABAergic neurons including glutamic acid decarboxylase, endogenous GABA and synaptosomal uptake of [³H]GABA. The extrinsic hippocampal cholinergic and noradrenergic afferents also exhibit significant alteration. Although the specific activity of choline acetyltransferase is unaffected and the specific activity of tyrosine hydroxylase is significantly increased in the injected hippocampus, the synaptosomal high affinity uptake process for [³H]choline and [³H]norepinephrine are significantly reduced at 10 days after injection. Whereas the level of endogenous acetylcholine is elevated in the lesioned hippocampus at 2 days after injection, the level of endogenous norepinephrine is reduced. For several hours after intrahippocampal injections of 5 nmoles or more of kainate, rats exhibit epileptiform behavior. Intrahippocampal injection of kainate may be a useful rodent model for temporal lobe seizure disorders.     

Role of kynurenines in the neurotoxic actions of kainic acid

The neurotoxic actions of kainic acid can be partly suppressed by antagonists acting at N-methyl-D-aspartate (NMDA) receptors. The present study examined the possible role of endogenous components of the kynurenine pathway to this phenomenon. Administration of kainate (2 nmols) into the hippocampus of anaesthetized rats produced damage in the CA1 and CA3 regions. The involvement of NMDA receptors was confirmed by the ability of dizocilpine (1 mg kg(-1)) to reduce cell loss in the CA1 region from 92 to 42%. The co-administration of m-nitrobenzoylalanine (20 nmols into the hippocampus), an inhibitor of kynurenine hydroxylase and kynureninase, together with a systemic injection of the compound (100 mg kg(-1), i.p.), afforded some protection against kainate, reducing cell loss from 91 to 48%. Protection was not exerted against damage by quinolinic acid or NMDA, excluding a direct interaction between m-nitrobenzoylalanine and NMDA receptors. The protective effect of m-nitrobenzoylalanine was not prevented by glycine, which would be expected to reverse protection caused by an elevation in the levels of endogenous kynurenic acid, arguing against a major role for increased levels of kynurenic acid. The results indicate that inhibition of the kynurenine pathway offers protection against kainate-induced damage. One possible mechanism for the protection is that an increased production of quinolinic acid in the brain, possibly from glial cells and macrophages activated by the initial kainate insult, normally contributes to the local activation of NMDA receptors and thus to kainate-induced cerebral insults. This generation of endogenous quinolinic acid would be suppressed by m-nitrobenzoylalanine.     

Effects of L-glutamic acid and kainic acid on central cardiovascular control

L-Glutamic acid and kainic acid injected into the cisterna magna of dogs, produced a dose-dependent increase in blood pressure and a decrease in heart rate. In contrast, intravenous injection of both compounds was ineffective. The hypertension was probably due to an increase in sympathetic tone as guanethidine prevented the rise in blood pressure induced by central administration of L-glutamic acid and kainic acid. Kainic acid was 1 000 fold more potent than L-glutamic acid.     

Ca2+/calmodulin-dependent phosphoprotein phosphatase activity of calcineurin in rat striatum: effect of kainic acid lesions

Calcineurin, a Ca2+ and calmodulin (CM)-dependent phosphatase, has been shown to be present in high concentrations in the striatum. Using inhibitor-1(phosphorylated by cAMP-dependent protein kinase) as a substrate, we found Ca2+/CM-dependent phosphatase (calcineurin) to be more than 2-fold higher than non-Ca2+/CM-dependent phosphatase in the rat striatum. In order to determine the cellular localization of calcineurin, striatal kainic acid injections were used to destroy neurons whose cell bodies are present at the site of injection. Glutamic acid decarboxylase (GAD) activity was measured as an indicator of destruction of striatal GABA-ergic neurons. After intrastriatal injection of 1 and 2 ug of kainic acid, there was a significant decrease of both calcineurin and GAD. However, injection of 0.5 ug kainic acid into the striatum reduced GAD activity by 81%, but had no effect on calcineurin phosphatase activity. Thus calcineurin does not appear to be equally distributed among all types of striatal neurons, but rather may be concentrated in neurons that are less sensitive to kainic acid than the GABA-ergic neuron.     

Modification of drug-induced tremor by systemic administration of kainic acid and quisqualic acid in mice

The effects of excitatory amino acids, kainic acid and quisqualic acid, on the tremorine- and harmaline-induced tremor were quantitatively examined in mice using the power spectral analyzing method. The severity of the tremor was determined quantitatively in terms of the cumulative sum of the mean square value of the data. Kainic acid enhanced the tremor induced by tremorine but depressed the tremor induced by harmaline. Quisqualic acid depressed the tremor induced by both tremorine and harmaline in a dose-dependent manner. Kainic acid shifted the frequency of each component of the tremor induced by tremorine to the high frequency side, but quisqualic acid did not affect the frequency of tremor of the tremor induced by tremorine. The frequency of tremor of the tremor induced by harmaline was shifted by both excitatory amino acids to the low frequency side, and another component of tremor in the power spectral densities developed, of which the mean square values were very small. The present results suggest that, at least in part, the glutamatergic system can take a role on the modification of drug-induced tremor.     

7-chlorokynurenic acid prevents in vitro epileptiform and neurotoxic effects due to kainic acid

• 1.1. The effects of 7-chlorokynurenic acid were studied against the epileptiform and neurotoxic effects due to the non-NMDA excitatory amino acid, kainic acid, in rat hippocampal slices.
• 2.2. Slice perfusion with 7-chlorokynurenic acid (100 μM), significantly (p<0.05) decreased the duration of the CA1 epileptiform bursting due to 1 μM kainic acid.
• 3.3. Slice perfusion with 7-chlorokynurenic acid (100 μM) significantly (p<0.05) increased the probability of recovery of the CA1 population spike after a neurotoxic concentration (12 μM) of kainic acid.
• 4.4. The results indicate that 7-chlorokynurenic acid affects, with a similar potency, epileptiform and neurotoxic effects due to kainic acid.

     

Effects of kainic acid analogues on crayfish opener muscle.

The depolarizing action of ten analogues of kainic acid was investigated using the crayfish neuromuscular preparation. The most potent excitant of these compounds was domoic acid. Domoic acid is a heterocyclic amino acid obtained from a seaweed. Chondria armata. The depolarizing action of bath-applied domoic acid was 5–10 times more potent than that of l-glutamate. The electrophoretic injection of domoic acid produced a slow and small depolarization and the sensitive area roughly overlapped the glutamate sensitive area. Domoic acid will be available as a useful pharmacological tool in addition to kainic acid.