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PubMed1987

Pentylenetetrazol-induced seizure is not mediated by benzodiazepine receptors in vivo.

The selective benzodiazepine antagonist RO 15-1788, labelled with carbon 11 [11C] RO 15-1788, as a specific marker, together with positron emission tomography, allows the in vivo study of benzodiazepine receptors in primates. In addition, when coupled with recordings of electroencephalographic activity, this method offers the feasibility of studying the correlation between occupancy of benzodiazepine receptors and the convulsant action of drugs acting at the benzodiazepine-GABA receptor complex in vivo. The present study showed that convulsant doses of pentylenetetrazol (PTZ) could affect the binding of [11C] RO 15-1788 in vivo in two ways, depending on the doses tested: at concentrations of 20 and 30 mg/kg, pentylenetetrazol increased the binding of [11C] RO 15-1788 whereas larger concentrations displaced the binding of [11C] RO 15-1788. The direct correlation between the occupancy of respective benzodiazepine receptors, afforded by increasing convulsant doses of pentylenetetrazol, revealed that competitive interaction with benzodiazepine receptors was not necessary for pentylenetetrazol to induce the appearance of seizures in vivo.

Animals↗

PubMed1989

Aspartame fails to facilitate pentylenetetrazol-induced convulsions in CD-1 mice.

Concentrations of plasma amino acids and brain monoamines as well as pentylenetetrazol-induced seizures were monitored in CD-1 mice treated with aspartame in acute oral doses from 0 to 2500 mg/kg. One hour after administration aspartame produced increases in plasma concentrations of phenylalanine and tyrosine and modest reductions in concentrations of brain serotonin and 5-hydroxyindole acetic acid. However, these effects of the sweetener had no influence on the convulsive dose fifty (CD50) of pentylenetetrazol. Moreover, aspartame failed to alter the percentage of mice exhibiting seizures when exposed to an approximate CD50 of pentylenetetrazol. Finally, aspartame had no effect on brain norepinephrine or dopamine concentrations. In sharp contrast to previously reported studies, these observations suggest that aspartame, given in heroic doses, does not alter the propensity to seizure activity in CD-1 mice. We conclude that changes in plasma amino acids and brain serotonin produced by large oral bolus doses of aspartame are insufficient to result in functional deficits which might have the capacity to facilitate pentylenetetrazol-induced seizures.

Amino Acids↗

PubMed1988

A study of pentylenetetrazol kindling in rats and mice.

The effect of repeated injection of pentylenetetrazol on pentylenetetrazol seizure thresholds was determined in mice and rats. Once per week treatment of rats with pentylenetetrazol resulted in the development of a state of kindling. On the other hand, when pentylenetetrazol was administered twice per week, a phenomenon resembling tolerance was observed. In mice, it was not possible to demonstrate kindling under experimental conditions utilizing either one or two treatments with PTZ per week.

Animals↗

PubMed1991

The effect of ofloxacin and ciprofloxacin on pentylenetetrazol-induced convulsions in mice.

There have been several reports that convulsions, although rare, occur in patients who received fluoroquinolones. In this study, conducted for the evaluation of the convulsant action of fluoroquinolones, the effect of ofloxacin and ciprofloxacin on pentylenetetrazol-induced convulsions were investigated in mice. Mice were pretreated intraperitoneally (IP) with saline, ofloxacin (20 or 80 mg/kg) or ciprofloxacin (20 or 80 mg/kg) 30 minutes before subcutaneous (SC) administration of pentylenetetrazol (40 or 60 mg/kg). In another experiment, diazepam (5 mg/kg) was injected (IP) in mice alone or in combination with ofloxacin (80 mg/kg) 30 minutes before pentylenetetrazol (40 mg/kg) administration (SC). In each experiment mice were observed over the following hour for the incidence and onset of clonic convulsions. Results showed that both doses of ofloxacin increased the incidence of clonic convulsions induced by 40 mg/kg pentylenetetrazol. This effect, however was only significant in the higher dose and inhibited by diazepam. On the other hand, a similar proconvulsant effect by ciprofloxacin could not be demonstrated.

Animals↗

PubMed1995

Kainate/AMPA receptor antagonists are anticonvulsant against the tonic hindlimb component of pentylenetetrazol-induced seizures in developing rats.

Non-NMDA receptor antagonists CNQX, DNQX, and NBQX (10-40 mg/kg IP) were tested against pentylenetetrazol-induced (100 mg/kg SC) seizures in 7 to 90-day-old rats. All three drugs significantly decreased the incidence of tonic hindlimb component of tonic-clonic pentylenetetrazol seizures, often in favor of increased incidence of forelimb tonus throughout development. In addition, in 7 to 25-day-old rats, DNQX and NBQX decreased the severity of seizures due to a decrease in total incidence of the tonic component of tonic-clonic seizures compared to age-matched controls. However, neither drug was able to consistently suppress the incidence or increase latency to onset of clonic and tonic-clonic pentylenetetrazol seizures. The data suggest that, during development, non-NMDA receptor transmission may play a role in the generation of the tonic component, but not in the generation of other components of pentylenetetrazol-induced seizures.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1994

Specific [3H]L-glutamate binding and [3H]D-aspartate release in the hippocampus of rat after pentylenetetrazol kindling and long-term potentiation.

In the present study, the time-course of changes in glutamate binding and aspartate release in the rat hippocampus following tetanization of perforant pathway and of pentylenetetrazol-induced kindling was investigated. The K+ (48 mM)-stimulated [3H]D-aspartate release from hippocampal slices and the specific [3H]L-glutamate binding to crude synaptic membranes of the hippocampus were measured 1, 4 and 24 h after the last tetanization train or one, five and nine weeks after the last pentylenetetrazol injections, respectively. The tetanization of the fascia dentata was followed by a significant increase in K(+)-stimulated [3H]D-aspartate release from hippocampal slices only 1 h after the last tetanization train, but the specific [3H]L-glutamate binding was enhanced 4 h afterwards. No further deviations from controls have been seen 24 h after tetanization. After pentylenetetrazol kindling, the K(+)-stimulated amino acid release from hippocampal slices was not changed. However, at one week as well as at five and nine weeks after the pentylenetetrazol kindling the specific [3H]L-glutamate binding in the hippocampus was significantly increased by about 50% compared to controls. From these findings it can be assumed that after long-term potentiation induction presynaptic transmitter release and post- (and/or pre-)synaptic glutamate binding are elevated with a different time course only in the early phase of potentiation. In contrast, kindling results in a long lasting increase in activity state of glutamatergic transmission. Therefore, it can be concluded that differences of the synaptic excitability following long-term potentiation and kindling are reflected by a different activation of glutamatergic system in the central nervous system.

Animals↗

PubMed1995

Excitatory amino acid antagonists and pentylenetetrazol-induced seizures during ontogenesis: III. The action of kynurenic acid and glutamic acid diethylester.

N-methyl-D-aspartate (NMDA) receptor antagonists are anticonvulsant drugs with specific activity against tonic-clonic pentylenetetrazol-induced seizures. However, they do not affect clonic seizures with preserved righting reflexes. In these experiments, we tested the anticonvulsant activity of strychnine-insensitive glycine receptor (at the NMDA site) antagonist kynurenic acid and nonspecific excitatory amino acid receptor antagonist glutamic acid diethylester (GDEE) in the pentylenetetrazol-induced seizure model in developing rats 7, 12, 18, 25, and 90 days old. Control rats were injected with pentylenetetrazol (100 mg/kg subcutaneously). Other rats were pretreated either with kynurenic acid (40, 80, or 240 mg/kg IP) or with GDEE (0.48-480 mg/kg IP), followed by pentylenetetrazol (100 mg/kg). In very young rats (7 and 12 days), both kynurenic acid and GDEE increased the incidence of clonic seizures, whereas the occurrence of tonic-clonic seizures was suppressed or delayed compared to controls. This effect is very similar to the anticonvulsant action of the competitive and noncompetitive NMDA receptor antagonists. In adult rats, the pretreatment with rather higher doses of kynurenic acid or GDEE suppressed or delayed clonic seizures as well as tonic-clonic seizures. Both drugs also induced behavioral side effects: repetitive orientation, wet dog shakes, and frequent jumping. Our data show that there are only weak and nonconsistent age-specific anticonvulsant effects resulting from the blockade of strychnine-insensitive glycine receptor often associated with serious side effects, thus decreasing chances to develop effective antiepileptic treatment in this drug class.

Age Factors↗

PubMed1994

gamma Aminobutyric acid mediation of the anticonvulsant effect of clonidine on pentylenetetrazol-induced seizures in mice.

The effects of muscimol, amino-oxyacetic acid (AOAA), diamino-N-butyric acid (DABA), bicuculline, picrotoxin, diazepam and phenobarbitone on the protective effect of clonidine against pentylenetetrazol-induced seizures were studied in mice. Muscimol, AOAA, DABA, phenobarbitone and diazepam significantly protected mice against pentylenetetrazol-induced seizures and also significantly potentiated the protective effect of clonidine against the seizures. Bicuculline and picrotoxin significantly potentiated seizures induced by pentylenetetrazol and significantly attenuated both the protective effects of muscimol and clonidine against the seizures. These data suggest that activation of gamma-aminobutyric acid systems may underlie the protective effect of clonidine against seizures induced by pentylenetetrazol in mice.

Animals↗

PubMed2003

Effects of clobenpropit on pentylenetetrazole-kindled seizures in rats.

The purpose of this study was to investigate whether or not clobenpropit, a selective and potent histamine H(3) receptor antagonist, can protect from pentylenetetrazole (35 mg/kg)-kindled seizures in rats. I.c.v. injection with clobenpropit (10 and 20 microg) significantly delayed the seizure stage and prolonged the latency to the onset of myoclonic jerks and the latency to the clonic generalized seizure in a dose-dependent manner. The protection by clobenpropit (20 microg) was completely antagonized by both immepip (5 and 10 microg, i.c.v.), a selective potent histamine H(3) receptor agonist, and alpha-fluoromethylhistidine (alpha-FMH, 50 microg, i.c.v.), a selective histidine decarboxylase inhibitor. In addition, clobenpropit markedly potentiated the histidine (100 and 200 mg/kg)-induced inhibition of pentylenetetrazole-kindled seizures. Pyrilamine (2 and 5 microg, i.c.v.) reversed the inhibition of pentylenetetrazole-kindled seizures induced by clobenpropit, whereas cimetidine had no effect even at a high dose of 5 microg. These results indicate that clobenpropit protects against pentylenetetrazole-kindled seizures in rats, and that its action is mainly due to the activation of endogenous histamine by blocking autoinhibitory presynaptic histamine H(3) receptors.

Animals↗

PubMed2005

Development of a pentylenetetrazole-induced seizure model to evaluate kinase inhibitor efficacy in the central nervous system.

c-Jun N-terminal kinases (JNKs) are implicated in cell death in neurodegenerative disorders. Therefore, JNK inhibitors could act as neuroprotective agents. To evaluate potential candidates, reproducible and quantitative CNS in vivo models are required. To that end, a pentylenetetrazole-induced seizure model was explored. c-Jun phosphorylation was detected in hippocampal extracts by blotting c-Jun immunoprecipitates with phosphorylation-specific antibodies. Pentylenetetrazole administration induced rapid and reproducible increases in c-Jun phosphorylation. However, special attention had to be paid to the composition of the extraction buffer to ensure stabilization of protein phosphorylation, as demonstrated using internal standards of phosphorylated recombinant c-Jun. As JNK and its upstream activator MKK4 are activated by phosphorylation, these events were also evaluated. In principle, kinase inhibitors could act at the level of JNK or upstream kinases to inhibit c-Jun phosphorylation. MKK4 phosphorylation was dramatically increased in response to pentylenetetrazole but, again, only when appropriate phosphatase inhibitors were in the extraction buffer. In contrast, JNK was found to be constitutively phosphorylated and unaltered upon pentylenetetrazole treatment. The JNK inhibitor SP600125 was shown to inhibit c-Jun phosphorylation without affecting MKK4 phosphorylation. Our procedures enable analysis of JNK pathway signalling in a CNS model and, also, should be applicable to that of other protein phosphorylation events in vivo.

Animals↗

PubMed2006

Amphetamine and pentylenetetrazole given post-trial 1 enhance one-trial tolerance to the anxiolytic effect of diazepam in the elevated plus-maze in mice.

There are several hypotheses to explain the lack of an anxiolytic effect on animals with previous maze experience (one-trial tolerance). Some of these hypotheses are related to learning and memory, so the reduction of trial 1 duration to 1 min or amnesic drug administration before trial 1 prevents the lack of an anxiolytic effect in trial 2. Amphetamine and pentylenetetrazole have been shown to enhance memory consolidation when administered immediately after training. Thus, the aim of the present study was to evaluate the effect of amphetamine (1.0-3.0 mg/kg) or pentylenetetrazole (30.0 mg/kg), at putative memory-enhancing doses, on the effect of diazepam (2.5 mg/kg) in the elevated plus-maze trial 2 on mice exposed to a 1-min long trial 1. Mice were submitted to 1-min trial 1 in the elevated plus-maze immediately followed by drug treatment (saline, amphetamine, or pentylenetetrazole) and to elevated plus-maze trial 2 after 48 h. Animals were treated with vehicle or diazepam 30 min before trial 2. The results showed that post-trial 1 saline and 1.0 mg/kg amphetamine did not induce one-trial tolerance. On the other hand, 2.0 and 3.0 mg/kg amphetamine and 30 mg/kg pentylenetetrazole induced a lack of anxiolytic effect of diazepam on trial 2 even with 1-min trial 1 length. Furthermore, these data were not due to novelty exposure in trial 1 or to amphetamine treatment so that mice exposed to an activity chamber instead of the plus-maze (trial 1) and then immediately submitted to amphetamine treatment (2.0 mg/kg) did not show one-trial tolerance 48 h after trial 1. Taken as a whole, these data support the hypothesis that memory is involved in the lack of an anxiolytic effect in the elevated plus-maze trial 2.

Amphetamine↗

PubMed1997

Recovery of decreased seizure threshold for pentylenetetrazole during diazepam withdrawal by NMDA receptor antagonists.

The effects of several NMDA receptor antagonists on pentylenetetrazole-induced diazepam-withdrawal seizure were examined in mice. The decrease in the seizure threshold for pentylenetetrazole during diazepam withdrawal was inhibited by pretreatment with MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate), 7-chlorokynurenic acid and ifenprodil. Furthermore, MK-801 and ifenprodil, at doses which did not affect the threshold of pentylenetetrazole-induced seizure in control mice, also significantly suppressed the decrease in the seizure threshold during diazepam withdrawal, whereas 7-chlorokynurenic acid did not. These findings suggest that overactivity of an ion channel site and an ifenprodil binding site on the NMDA receptor may play an important role in the hypersensitivity of pentylenetetrazole-induced seizure in diazepam-withdrawn mice.

Animals↗

PubMed1999

Role of metabotropic glutamate receptors in the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal.

To clarify the contribution of metabotropic glutamate (mGlu) receptors in brain to benzodiazepine withdrawal signs, we now examine the effects in mice of selective ligands for three subgroups of mGlu receptor on the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal. The seizure threshold for pentylenetetrazole was significantly decreased by the discontinuation of chronic diazepam treatment. The decrease in the seizure threshold for pentylenetetrazole during diazepam withdrawal was significantly suppressed by intracerebroventricular (i.c.v.) pretreatment with the group 1 mGlu receptor antagonist, (S)-4-carboxyphenylglycine ((S)-4CPG: 56 and 100 nmol). These doses of (S)-4CPG did not alter the seizure threshold in chronically vehicle-treated (control) mice. Pretreatment i.c.v. with a presynaptic mGlu receptor agonist (the group 2 mGlu receptor agonist (2S,1'S,2'S)-2-(carboxycyclopropyl)-glycine (L-CCG-I: 3.0 and 5.6 nmol) and the group 3 mGlu receptor agonist, L-amino-4-phosphonobutyric acid (L-AP4: 3.0 and 5.6 nmol)) failed to suppress the decrease in seizure threshold in diazepam-withdrawn mice, but increased the seizure threshold in control mice. Pretreatment i.c.v. with the group 1 mGlu receptor antagonist/group 2 mGlu receptor agonist, (S)-4-carboxy-3-hydroxyphenylglycine ((S)-4C3HPG: 56 and 100 nmol), significantly increased the seizure threshold in control mice and suppressed the decrease in seizure threshold in diazepam-withdrawn mice. These findings suggest that enhancement of group 1 mGlu receptor function and a decline in both group 2 and group 3 mGlu receptor functions may play an important role in the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal.

Animals↗

PubMed2000

Differential responses of phosphorylated mitogen-activated protein kinase and phosphorylated cyclic-AMP response element-binding protein immunoreactivity in the rat brain to sub-convulsive pentylenetetrazol.

The possible advantage of using multiple phospho-specific antibodies to study changes in brain activity was assessed. For this purpose, rats were injected intraperitoneally with either a control treatment or 15 mg/kg pentylenetetrazol. The sub-convulsive dose of pentylenetetrazol did not induce marked behavioural effects. Ten minutes after treatment, the rats were perfused and the brains were dissected. Adjacent brain sections were immunohistochemically stained for phosphorylated cyclic-AMP response element-binding protein and phosphorylated mitogen-activated protein kinase. Opposite effects of pentylenetetrazol treatment were observed on the immunoreactivity of these two antibodies within the hypothalamic paraventricular nucleus, the supraoptic nucleus and the arcuate nucleus. In these regions, pentylenetetrazol treatment increased phosphorylated mitogen-activated protein kinase immunoreactivity, but decreased phosphorylated cyclic-AMP response element-binding protein immunoreactivity. These findings show that changes in the activity of a brain nucleus can be accompanied by differential changes in the activity of two signal transduction pathways, which can be detected immunohistochemically. Therefore, the use of multiple phospho-specific antibodies may enhance our potential to monitor changes in brain activity.

Animals↗

PubMed1999

Anomalous expression of microtubule-associated protein 1B in the hippocampus and cortex of aged rats treated with pentylenetetrazole.

The aim of the present study was to assess the age-dependent response of microtubule-associated protein 1B, a plasticity-associated protein deriving from a late gene, following administration of an epileptogenic stimulus. The effect of a single administration of the convulsant pentylenetetrazole on microtubule-associated protein 1B expression in the hippocampal formation and cortex of three-, 18- and 28-month-old rats was assessed using northern blot analysis, in situ hybridization and immunohistochemistry. In three-month-old rats, we detected initial increases in microtubule-associated protein 1B messenger RNA at 15 h following pentylenetetrazole administration in the granule cells of the dentate gyrus, in the CA3 region of the hippocampus and in layers II/III of the entorhinal cortex, and these reached a maximum at 44 h. However, in the hippocampus and cortex of 18-month-old rats, the peak occurred at 15 h, and in the brains of 28-month-old rats a blunted peak was reached at 3 h. Pentylenetetrazole treatment in young rats resulted in a robust induction of microtubule-associated protein 1B immunoreactivity in the granule cells of the dentate gyrus and in layers II/III of the entorhinal cortex, but also produced a large decrease in the retrosplenial cortex. However, following pentylenetetrazole treatment in older rats, the granule cells of the dentate gyrus were nearly devoid of microtubule-associated protein 1B immunoreactivity, whereas the retrosplenial cortex showed no changes at all, and the entorhinal cortex had an expression pattern similar to that of young rats. Aberrant immunolabeling of microtubule-associated protein 1B occurred in cortical layer VI of the aged rats where, unlike in young rats, there was heavy staining of neuronal somata. These results suggest that the regulation of the plasticity-associated protein microtubule-associated protein 1B is altered in the ageing rat brain, with the peak of expression shifted to earlier times in 18-month-old rats and blunted, variable increases at even earlier times in 28-month-old rats.

Aging↗

PubMed2000

Effect of shitei-to, a traditional Chinese medicine formulation, on pentylenetetrazol-induced kindling in mice.

This study measured the effects of Shitei-To (STT), a traditional Chinese Medicine, which is a mixture of extracts from three medicinal herbs, Shitei (SI, Kaki Calyx; calyx of Diospyros kaki L. f.), Shokyo (SK, Zingiberis Rhizoma; rhizome of Zingiber officinale Roscoe) and Choji (CJ, Caryophylli flos; flowerbud of Syzygium aromaticum [L.] Merrill et. Perry), has long been used for the treatment of hiccups in Japan and China, against fully pentylenetetrazol-kindled seizures and on the development of pentylenetetrazol kindling in mice. Repeated administration of STT (3.0 g/kg p.o.) mildly retards the development of pentylenetetrazol-induced kindling in mice. STT also decreased the number of tonic-clonic convulsions resulting from progression kindling. On the other hand, STT had no effect on convulsions in fully pentylenetetrazol-kindled mice. These findings suggest that STT protects against the development of convulsions, and that STT may have therapeutic effects in the prevention of secondarily generalized seizures.

Animals↗

PubMed1981

Lidocaine and pentylenetetrazol seizure thresholds in cats are not reduced after enflurane anesthesia.

Some previous reports indicate that the excitability of the brain may be increased for days following enflurane anesthesia. The authors investigated this possibility in cats by determining whether or not pentylenetetrazol- (Metrazol) or lidocaine-seizure thresholds decreased after repeated enflurane exposure. The lidocaine-seizure threshold was bracketed in 4 cats, and the pentylenetetrazol-seizure threshold was bracketed in another 4 cats. Each cat was then exposed to 4 per cent enflurane for 2 hours on 4 successive days. Twenty-four hours after the last enflurane exposure, the cats were injected with the previously determined subthreshold dose of pentylenetetrazol (6.4 mg/kg, on the average) or lidocaine (7.8 mg/kg, on the average). No cat convulsed. It was therefore concluded that under our experimental conditions, repeated enflurane exposure does not increase the sensitivity to drugs which nonselectively excite the central nervous system (e.g., pentylenetetrazol) or to drugs which mimic temporal lobe epilepsy (e.g., lidocaine). This finding cast doubt that brain excitability is increased in the post-enflurane anesthetic period.

Anesthesia↗

PubMed1976

Specific and nonspecific multiple unit activities during the onset of pentylenetetrazol seizures. II. Acute lesions interrupting nonspecific system connections.

Nonspecific cortical, thalamic, mesencephalic, and pontine multiple unit activities (MUA) and changes in EEG and MUS of the sciatic nerve after threshold pentylenetetrazol activation were studied in three groups of animals in which neuronal connections were interrupted at three different levels of the central nervous system: spinal, mesencephalic, and prethalamic. Maximal increments of nonspecific MUA and maximal increments and maximal decrements of sciatic MUA after pentylenetetrazol from each group of lesioned animals were statistically compared with tose observed in intact animals. 1. Pentylenetetrazol threshold for producing cortical tonic-clonic EEG discharges was increased in animals with nesencephaic and prethalamic lesions but was not modified in animals with spinal transection. 2. Cortical MUA maximal increment was significantly decreased in mesencephalic and prethalamic lesioned animals, whereas thalamic MUA maximal increment was significantly decreased in mesencephalic and significantly increased in prethalamic lesioned animals. Pontine MUA maximal increment was significantly increased in spinal, mesencephalic, and prethalamic lesioned animals, and mesencephalic M-A maximal increment was not significantly modified in either prethalamic lesioned or in spinal transected animals. 3. Sciatic MUA maximal increment and maximal decrement were significatly decreased in spinal transected animals, whereas only maximal increment was significantly decreased in mesencephalic and only maximal decrement was significantly decreased in prethalamic lesioned animals. These results based on lesion experiments permit us to infer than under normal cinditions the development of generalized seizures induced by threshold pentylenetetrazol injection is highly dependent upon the neuronal interactions between nonspecific structures at different levels of the central nervous system. The possible nature of these neuronal interactions in the intact animals is discussed.

Animals↗