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PubMed1977

Comparison of effects of bicuculline, strychnine, and picrotoxin with those of pentylenetetrazol on photically evoked afterdischarges.

The effects of bicuculline, strychnine, and picrotoxin on photically evoked afterdischarges (PhADs) in rat visual cortex were compared with those of pentylenetetrazol (a known PhAD potentiator) and a diazepam (a known PhAD suppressor) challenge. Bicuculline was found to augment PhADs in a manner similar to that found with pentylenetetrazol, with the exception that potentiation only occurred at convulsive levels whereas pentylenetetrazol augmentation occurred at both subconvulsive and convulsive levels. Diazepam suppressed bicuculline-potentiated PhADs. Picrotoxin was found to have some limited augmenting effect on PhAD activity but in a manner unlike that observed with either bicuculline or pentylenetetrazol. Strychnine had no systematic augmenting effect on PhADs. These results were discussed in terms of the possible role of GABA in thalamic systems responsible for PhAD production.

Animals↗

PubMed1988

Pentylenetetrazole inhibits glutamate dehydrogenase and aspartate aminotransferase, and stimulates GABA aminotransferase in homogenates from rat cerebral cortex.

The mechanism by which pentylenetetrazole provokes convulsions in animals has been investigated by measuring its influence in vitro on the activities of several enzymes of glutamate metabolism in rat brain homogenates. Pentylenetetrazole does not affect the specific activities of glutamine synthetase, glutaminase, or glutamate decarboxylase; it inhibits those of glutamate dehydrogenase and aspartate aminotransferase, and stimulates that of gamma-aminobutyric acid (GABA) aminotransferase. The overall consequence of the action of pentylenetetrazole on the activities of these enzymes should be an increase in the concentration of glutamate and a decrease in that of GABA. This modulation of glutamate and GABA metabolism by pentylenetetrazole could contribute to the triggering of convulsions.

4-Aminobutyrate Transaminase↗

PubMed1989

Ethosuximide affects both pentylenetetrazole- and kainate-induced clonic seizures but differentiates between tonic-clonic seizures.

Young (25-day-old) and adult (90-day-old) rats pretreated with ethosuximide (62.5 or 125 mg/kg i.p.) were injected with either s.c. pentylenetetrazole (100 mg/kg) or i.p. kainate (10 or 14 mg/kg). The incidences and latencies of minor (clonic) and major (tonic-clonic) seizures were registered. Ethosuximide (125 mg/kg) completely blocked clonic seizures induced by the lower dose of kainate, and slightly suppressed or delayed those induced by the higher dose of kainate or pentylenetetrazole in both age groups. The effect of ethosuximide on major kainate-induced seizures (elicited in young rats only) was insignificant (ethosuximide only partially decreased the incidence of major seizures), whereas ethosuximide abolished major pentylenetetrazole-induced seizures in both age groups. Ethosuximide also failed to affect the latencies of kainate-induced automatisms (e.g., scratching, wet dog shakes). Similarities between kainate- and pentylenetetrazole-induced clonic seizures, as well as a similar action of ethosuximide on both, suggest a common generator for the pattern of clonic seizures.

Animals↗

PubMed1982

Hypophyseal hormone levels in blood and cerebrospinal fluid in response to histamine and pentylenetetrazol.

Histamine administered intraperitoneally increased, in a dose-dependent manner, AVP, OXT and PRL levels in plasma of rats, whereas alpha-MSH levels were not affected. Levels of AVP in plasma after histamine 20.0 mg/kg treatment were approximately 100-fold higher than those of controls, while OXT and PRL levels were approximately 7-fold higher after this treatment. CSF content of AVP, OXT, PRL and alpha-MSH was not influenced by histamine, indicating that a stimulated release of hormones from the pituitary into the blood is not accompanied by a concomitant increase of secretion of these hormones into the CSF. Convulsions induced by pentylenetetrazol were accompanied by a temporary increase in AVP levels and by strongly and consistently elevated OXT levels in plasma. PRL and alpha-MSH plasma levels were affected in a biphasic manner. A convulsion type 1 induced elevated PRL levels and diminished alpha-MSH levels, while a convulsion type 2 had no effect on plasma PRL concentration, but increased the concentration of alpha-MSH. Only the level of OXT in CSF was increased after a pentylenetetrazol-induced convulsion type 1. The present data suggest that histamine affects the release of AVP, while pentylenetetrazol might act more specifically on the OXT-releasing system. Furthermore, a possible relationship between the pentylenetetrazol-induced increase of OXT levels in the CSF and amnesia is suggested.

Animals↗

PubMed1985

Does the benzodiazepine antagonist Ro 15-1788 reverse the actions of picrotoxin and pentylenetetrazole on social and exploratory behaviour?

The effects of the benzodiazepine receptor antagonist, Ro 15-1788, were examined in combination with those of picrotoxin and pentylenetetrazole on social and exploratory behaviour in the rat. Both Ro 15-1788 (10 mg/kg) and picrotoxin (2 mg/kg) reduced social interaction, but there was no additive effect of these drugs together. Ro 15-1788 (10 and 20 mg/kg, which had no intrinsic effects in the holeboard alone) antagonized the reductions in exploratory head-dipping and motor activity produced by low (2 mg/kg), but not by high (4 mg/kg), doses of picrotoxin. In contrast, pentylenetetrazole (20 mg/kg) enhanced the reduction in social interaction produced by Ro 15-1788 (10 mg/kg), in accordance with previous findings that the reductions in spontaneous behaviour in the holeboard produced by pentylenetetrazole are enhanced by Ro 15-1788. These results show that there are clear functional interactions between these two compounds at the GABA-benzodiazepine receptor complex in the CNS, and that the nature of these interactions differs for picrotoxin and pentylenetetrazole.

Animals↗

PubMed1995

Behavioural effects of novel benzodiazepine (omega) receptor agonists and partial agonists: increases in punished responding and antagonism of the pentylenetetrazole cue.

In recent years a number of novel compounds have been described with affinity and specificity for BZ (omega) receptors. While some of these agents appear to act, like benzodiazepines themselves, as full agonists at different receptor subtypes (e.g. suriclone), several non-selective partial agonists (e.g. bretazenil) have been described, as have a number of BZ(1) (omega(1)) selective drugs (e.g. zolpidem). Previous work has reported a number of differences between the behavioural effects of some of these drugs and those of benzodiazepines; however, very few studies have attempted systematic comparisons of a large number of drugs in different procedures. In the present study a wide range of BZ (omega) receptor ligands was studied using two behavioural methods in rats: unpunished and punished food-reinforced operant responding and the discriminative stimulus effects of pentylenetetrazole. Punished operant responding showed increases with the benzodiazepines, chlordiazepoxide and clorazepate, the non-benzodiazepines, saripidem, CL 273,547 and F 2692 (limited effect at a single dose) and the partial agonists bretazenil and Ro 19-8022, but the BZ(1) selective agents, alpidem, abecarnil and CL 284,846, did not increase rates of punished operant responding. Rates of unpunished responding were decreased by higher doses of all drugs except bretazenil and Ro 19-8022. Dose-related antagonism of the pentylenetetrazole (18mg/kg) discriminative stimulus was produced by several benzodiazepines, by the partial agonists bretazenil, Ro 19-8022 and divaplon, and by suriclone, saripidem and CL 273,547. The BZ(1) (omega(1)) selective drugs abecarnil, CL 284,846, zolpidem, CL 218,872 and alpidem were also active in blocking pentylenetetrazole but produced only partial antagonism which was not clearly dose-related. The results show that novel BZ (omega) receptor ligands do not always produce a behavioural profile identical to that shown by benzodiazepines. In particular, BZ(1) (omega(1)) selective drugs do not give rise to clear increases in punished operant responding and have only limited efficacy in blocking the pentylenetetrazole cue. These effects may be due to the marked propensity of BZ(1) (omega(1)) selective drugs to decrease operant response rates.

Journal Article↗

PubMed1976

Pentylenetetrazol-induced amnesia: a case for overt seizures.

In this study, the possible role of overt convulsions following pentylenetetrazol (PTZ) in retrograde amnesia was investigated. Following a single passive avoidance conditioning, when overt convulsions were blocked with sodium pentobarbital (Nem), the amnesic effect of pentylenetetrazol was also blocked. Subconvulsive doses of the drug did not produce amnesia. Animals that received a typically convulsive dose of the drug but failed to convulse were not amnesic; only animals with overt convulsions were different from saline controls. The data suggest that overt convulsions may be necessary for the development of pentylenetetrazol-induced retrograde amnesia.

Amnesia↗

PubMed1982

Pentylenetetrazole induced changes in cerebellar energy metabolism.

Pentylenetetrazole was administered to Swiss-Albino mice, producing clonic-tonic seizures. Other groups were pretreated with one of the three anticonvulsants: phenytoin, clonazepam, or sodium valproate. Mice were sacrificed during the preseizure (1 minute) stage and at the onset of clonic-tonic seizures (2 minutes). Glucose, glycogen, ATP, and phosphocreatine were measured in layers of the parietal cortex and cerebellar vermis. Cortical metabolites were unchanged, or increased slightly, suggesting decreased utilization. In both cerebellar layers, glucose and glycogen were significantly decreased, and phosphocreatine was decreased in the molecular layer. These results indicate a regionally selective effect for pentylenetetrazole on cerebral energy metabolites. Pretreatment with anti-convulsants reduced the severity of the seizure, and eliminated the effect of pentylenetetrazole on glucose and glycogen.

Adenosine Triphosphate↗

PubMed1983

Bidirectional effects of benzodiazepine receptor ligands against picrotoxin- and pentylenetetrazol-induced seizures.

The dose response curves of picrotoxin-induced seizures and pentylenetetrazol-induced seizures were shifted to the right by the benzodiazepine (BZ) receptor agonist lorazepam, and to the left by the inverse agonists, DMCM, ZK 90886, FG 7142 and CGS 8216. The BZ receptor antagonists ZK 93426 and Ro 15-1788 had no effect on the dose response curves. The anticonvulsive action of lorazepam and the proconvulsive action of DMCM against picrotoxin-induced seizures and against pentylenetetrazol-induced seizures was inhibited by low doses of ZK 93426 and Ro 15-1788. These results indicate that the bidirectional effects of benzodiazepine receptor ligands on picrotoxin and pentylenetetrazol induced seizures is actually mediated through benzodiazepine receptors.

Animals↗

PubMed1996

Influence of nicardipine, nimodipine and flunarizine on the anticonvulsant efficacy of antiepileptics against pentylenetetrazol in mice.

Among three calcium channel inhibitors, only nicardipine (10-40 mg/kg) significantly inhibited clonic seizures induced by pentylenetetrazol administered at its CD97 (convulsive dose 97%) of 81 mg/kg, subcutaneously. Nimodipine and flunarizine (both up to 80 mg/kg) did not suppress pentylenetetrazol-induced clonic seizures per se. Co-administration of nicardipine (5 mg/kg) resulted in a significant enhancement of the protective potency of either ethosuximide (50 mg/kg) or valproate (100 mg/kg) against clonic seizures in this test. Similar effects were noted in case of combined treatment of nimodipine (20-40 mg/kg) with these antiepileptics. On the contrary, flunarizine (up to 20 mg/kg) did not modify the anticonvulsive action of these antiepileptic drugs. Moreover, none of the studied calcium channel inhibitors influenced the protective activity of clonazepam (0.01 mg/kg). The antiepileptic drugs, administered alone in above doses, were ineffective against pentylenetetrazol-induced clonic convulsions. In case of ethosuximide and valproate, the motor performance in the chimney test was worsened by co-administration of nimodipine (40 mg/kg). We found no pharmacokinetic interactions (at least in relation to the plasma levels of ethosuximide and valproate) that could explain the observed results. Thus, we conclude that a combination of some calcium channel inhibitors and antiepileptic drugs may provide more efficient protection against experimental seizures which may bear a potential clinical significance.

Animals↗

PubMed2006

Pentylenetetrazol kindling in rats: Is neurodegeneration associated with manifestations of convulsive activity?

Structural changes in neurons and measures of oxidative stress were studied in the hippocampus of rats tolerant (ST) and sensitive (SS) to developing clonic-tonic seizures in conditions of pentylenetetrazol kindling. Sequences of 11 injections of pentylenetetrazol significantly decreased the number of normal neurons in hippocampal field CA1 in SS rats, this effect being seen in both hippocampal field CA1 and the dentate fascia in ST rats. Decreases in the numbers of normal neurons were accompanied by increases in the numbers of damaged cells in field CA4 in rats of both groups. After 21 injections, decreases in the numbers of normal neurons were seen in field CA1 in both SS and ST rats, while the numbers of damaged neurons were significantly greater than control only in ST rats in fields CA1 and CA4. The glutathione level was significantly lower in the hippocampus in both groups of rats than in controls. Thus, rats " tolerant" to developing convulsions show signs of oxidative stress and neurodegenerative changes in the hippocampus. This suggests that oxidative neuron damage leading to neurodegeneration in the pentylenetetrazol kindling model is not directly associated with convulsive activity.

Animals↗

PubMed1992

Activation of the dentate gyrus by pentylenetetrazol evoked seizures induces mossy fiber synaptic reorganization.

Kindled seizures evoked by electrical stimulation of limbic pathways in the rat induce sprouting and synaptic reorganization of the mossy fiber pathway in the dentate gyrus (DG). To investigate whether seizures evoked by different methods also induce reorganization of this pathway, the distribution of mossy fiber terminals in the DG was examined with Timm histochemistry after systemic administration of pentylenetetrazol, a chemoconvulsant that reduces Cl- mediated GABAergic inhibition. Myoclonic seizures evoked by subconvulsant doses of pentylenetetrazol (24 mg/kg i.p.) were not accompanied by electrographic seizures in the DG, and did not induce mossy fiber sprouting. Generalized tonic-clonic seizures evoked by repeated administration of PTZ (24 mg/kg i.p.) were consistently accompanied by electrographic seizure activity in the DG, and induced sprouting and synaptic reorganization of the mossy fiber pathway. The results demonstrated that repeated generalized tonic-clonic seizures evoked by pentylenetetrazol induced mossy fiber synaptic reorganization when ictal electrographic discharges activated the circuitry of the DG.

Animals↗

PubMed1983

The partial benzodiazepine agonist properties of Ro 15-1788 in pentylenetetrazol-induced seizures in cats.

The effects of Ro 15-1788, a specific benzodiazepine antagonist, were studied on pentylenetetrazol-induced seizures in cats. Ro 15-1788 decreased the number of myoclonic jerks induced by a subconvulsive dose of pentylenetetrazol (12.5 mg/kg, i.m.). Ro 15-1788 suppressed generalized convulsive seizures induced by a minimal convulsive dose of pentylenetetrazol (25-35 mg/kg), but did not block the effects of higher doses (35-45 mg/kg). These results indicate that Ro 15-1788 is not a pure benzodiazepine antagonist, but has partial agonistic properties.

Animals↗

PubMed1983

Potentiation of hyperthermia-induced convulsions in the developing rat by previous treatment with pentylenetetrazol.

Infant rats were subjected to pentylenetetrazol-induced convulsions on alternate days from 5 to 13 days of age. At 17 days of age, their susceptibility to the convulsant effects of hyperthermia was examined. It was found that previous pentylenetetrazol-induced convulsions caused a significant facilitation in the development of hyperthermia-induced convulsions. The development of hyperthermia-induced convulsions was also facilitated in rat pups of a similar age after acute pretreatment with a subconvulsive dose of pentylenetetrazol. The results of this study indicate that cross sensitization between convulsant agents is possible in the developing rat. In addition, although the nervous system of the immature rat is not fully developed, the central substrates of this process evince adultlike characteristics.

Animals↗

PubMed1986

Modification of electroshock and pentylenetetrazol seizure patterns in rats after precollicular transections.

Rats with precollicular transections leaving the brain stem intact were subjected to electroshock or pentylenetetrazol-induced convulsions. Animals with transections failed to display the face and forelimb clonus (with or without rearing) typically seen in sham-operated rats subjected to pentylenetetrazol- or minimal electroshock-induced convulsions elicited with corneal electrodes. Moreover, rats with transections exhibited all other components of pentylenetetrazol- and electroshock-induced seizures. These findings support the hypothesis that tonic and some types of clonic convulsions can occur independently of seizure discharge in forebrain structures, whereas clonus restricted to the face and forelimbs depends on seizure discharge emanating from structures within the forebrain for expression.

Animals↗

PubMed1986

Enhanced bursting activity in the CA3 region of the mouse hippocampal slice without long-term potentiation in the dentate gyrus after systemic pentylenetetrazole kindling.

The repeated administration of subconvulsant doses of pentylenetetrazole (24 mg/kg, i.p.) produced chemically kindled seizures in 16 of 20 mice. Hippocampal slices prepared from the mice with kindled seizures were tested for input-output characteristics in the dentate gyrus, and for spontaneous burst discharge frequency in area CA3. The kindled slices displayed no change in the magnitude of the evoked granule cell excitatory postsynaptic potential (pEPSP) to a given stimulus intensity applied to the perforant path, nor in magnitude of the granule cell population spike for a given pEPSP. Although long-term potentiation of synaptic transmission has been proposed as the cellular mechanism of kindling, these results indicate either that long-term potentiation may not underlie kindling or that systemic pentylenetetrazole kindling and focal electrical kindling may be accomplished by different mechanisms. Hippocampal slices from kindled animals did, however, show an increased incidence of spontaneous burst discharges in area CA3 pyramidal neurons in both the absence and the presence of pentylenetetrazole in the bathing medium.

Action Potentials↗

PubMed1987

Modification of amygdala-kindled postictal inhibition by pentylenetetrazol and diazepam.

When fully amygdala-kindled rats are electrically stimulated in grouped trials with intertrial stimulation intervals of less than 60 min, significant residual inhibition can be demonstrated. When these grouped trials of stimulation are repeated daily, additional cumulative inhibition is seen. The present study examined the effect of daily pretreatment with three doses of pentylenetetrazol (5, 10, and 20 mg/kg) and two doses of diazepam (0.5 and 2 mg/kg) on daily, grouped trial electrical stimulations of fully amygdala-kindled rats. Little or no reduction was seen in postictal inhibition by pentylenetetrazol pretreatment including the highest dose tested in which prestimulation bursts of spiking were associated with short episodes of forelimb clonus. Pretreatment with the benzodiazepine receptor agonist, diazepam, resulted in a dose-dependent reduction in the first elicited seizure response each day compared with control trials. Subsequent daily seizure trials of diazepam-treated animals demonstrated a relatively constant degree of dose-dependent seizure suppression without evidence of further postictal inhibition. The neural substrate that governs grouped trial postictal inhibition of amygdala-kindled seizures appears to be resistent to modification by near-convulsant doses of pentylenetetrazol, an agent with a presumed GABA-mediated mechanism of action. Diazepam, an anticonvulsant with a presumed GABA-related or associated mechanism of action, suppressed seizures in a dose-dependent manner nearly equally across all trials.

Amygdala↗

PubMed1983

The effects of doxapram, diazepam, phenobarbital and pentylenetetrazol on suprathreshold and threshold stimulations in amygdaloid kindled rats.

Amygdaloid kindled rats were utilized to determine the effects of the respiratory stimulant, doxapram (7.5-60 mg/kg) on seizures elicited by suprathreshold or threshold electrical stimulation. For comparison, a single dose of pentylenetetrazol (30 mg/kg), phenobarbital (40 mg/kg) and diazepam (2 mg/kg) were also tested in the same paradigm. With suprathreshold stimulation, doxapram did not increase the intensity of seizures. Neither the afterdischarge duration (AD) nor the behavioral rank (BR) were increased with doses high enough to cause systemic signs of toxicity. Similarly, the convulsant pentylenetetrazol did not increase AD or BR after suprathreshold stimulation. The anticonvulsants phenobarbital and diazepam significantly reduced both AD and BR after suprathreshold stimulation. Seizure thresholds tended to be higher after the various doses of doxapram with no consistent effect on elicited AD or BR. Pentylenetetrazol did not change threshold values, but was found to increase AD and BR at threshold. Both phenobarbital and diazepam raised thresholds with a significant decrease in elicited AD and BR. It would appear that the respiratory stimulant doxapram has little proconvulsant activity in this model of epilepsy.

Amygdala↗