Administration Of Pentylenetetrazol Research Articles

P03-117 - Antiepileptic effects of quinine in the pentylenetetrazole model of seizure

IntroductionQuinine, is an anti-malarial drug that specifically blocks connexin 36 at gap junction channels.ObjectiveQuinine has suppressed ictal epileptiform activity in vitro without decreasing neuronal excitability.AimWe considered the possible anticonvulsant effects of quinine in the pentylenetetrazole (PTZ) model of seizure.MethodsIn five groups, the mice were given quinine at the doses of 20, 30, 40, 50, or 60 mg/kg 30 min before the administration of PTZ (90 mg/kg). Two groups were injected with diazepam, the positive control (0.5, 1 mg/kg) and one group, the control group, was injected with saline + Tween 80 before the administration of PTZ. The onset of a general clonus was used as the endpoint. The general clonus was characterized by forelimb clonus followed by full clonus of the body.ResultsIn the PTZ model, quinine at the dose of 60 mg/kg increased the latency of seizure. However, quinine at 40-60 mg/kg decreased the duration of seizure, dose dependently.ConclusionThe present study provides evidence for anticonvulsant activity of quinine in the generalized clonic seizure of PTZ model. As a result of these finding, we suggest that gap junctions represent an appropriate target for the development of drugs aimed at decreasing epileptiform synchronization and preventing epileptogenesis.

Effect of lamotrigine, oxcarbazepine and topiramate on cognitive functions and oxidative stress in PTZ-kindled mice

Cognitive impairment is frequently observed in epileptic patients. It has been seen that not only epilepsy but antiepileptic drugs also impair cognitive functions. The present study was undertaken to assess the effect of three anticonvulsants viz. lamotrigine (5 mg/kg, p.o.), oxcarbazepine (15 mg/kg, p.o.) and topiramate (10 mg/kg, p.o.) on cognitive function and oxidative stress during pentylenetetrazole (PTZ)-kindling in mice. Kindling was induced by the administration of PTZ (25 mg/kg, i.p.) on every alternate day till 5 weeks. Cognition was assessed after the development of kindling. Elevated plus maze (EPM) and passive avoidance response (PAR) tests were carried out after 24 h and 48 h of the last PTZ administration. After completion of behavioural tests malondialdehyde (MDA), glutathione levels, superoxide dismutase and catalase activity were measured as an indicator of oxidative stress. The results of the present study indicate that topiramate (10 mg/kg) administration to kindled animals increased transfer latency and decreased step-down latency in EPM and PAR tests, respectively. However, lamotrigine and oxcarbazepine did not alter the two parameters. Topiramate administration to kindled as well as non-kindled animals has shown increase in MDA and decrease in glutathione levels. Lamotrigine and oxcarbazepine did not show significant alteration in oxidative stress parameters. To conclude, long term administration of topiramate impairs cognitive functions during experimental epilepsy while lamotrigine and oxcarbazepine are safer.

The role of magnesium sulfate in prevention of seizures induced by pentylenetetrazole in rats

Magnesium sulfate (MgSO₄) has been used to prevent seizures in eclampsia. This study examined the central effects of MgSO₄ on different types of pentylenetetrazole (PTZ)-induced seizures. Male Wistar rats were submitted to intracerebroventricular (ICV) administration of MgSO₄ at different doses followed by intraperitoneal administration of PTZ. The latency to the onset of the first seizure induced by PTZ was significantly increased by ICV administration of MgSO₄ at a dose of 100 µg compared to the control treatment. In addition, the total period during which animals presented with seizures was significantly reduced at this dose of MgSO₄. Furthermore, the latency to the onset of the first partial complex seizure was significantly increased by the lowest dose of MgSO₄. However, a high dose of MgSO₄ had no effect or even potentiated the effect of PTZ. These results suggest that, depending on the dose, MgSO₄ may be important in prevention of epileptic seizures.

Experimental re-evaluation of flunarizine as add-on antiepileptic therapy

Background:Experimental studies have found several calcium channel blockers with anticonvulsant property. Flunarizine is one of the most potent calcium channel blockers, which has shown anticonvulsant effect against pentylenetetrazole (PTZ) and maximal electroshock (MES)-induced seizures. However, further experimental and clinical trials have shown varied results. We conducted a PTZ model experimental study to re-evaluate the potential of flunarizine for add-on therapy in the management of refractory epilepsy.Materials and Methods:Experiments were conducted in PTZ model involving Swiss strain mice. Doses producing seizures in 50% and 99% mice, i.e. CD50 and CD99 values of PTZ were obtained from the dose-response study. Animals received graded, single dose of sodium valproate (100–300 mg/kg), lamotrigine (3–12 mg/kg) and flunarizine (5–20 mg/kg), and then each group of mice was injected with CD99 dose of PTZ (65mg/kg i.p.). Another group of mice received single ED50 dose (dose producing seizure protection in 50% mice) of sodium valproate and flunarizine separately in left and right side of abdomen. Results were analysed by Kruskal–Wallis ANOVA on Ranks test.Results:As compared to control, sodium valproate at 250 mg/kg and 300 mg/kg produced statistical significant seizure protection. At none of the pre-treatment dose levels of lamotrigine, the seizure score with PTZ differed significantly from that observed in the vehicle-treated group. Pre-treatment with flunarizine demonstrated dose-dependent decrease in the seizure score to PTZ administration. As compared to control group, flunarizine at 20 mg/kg produced statistical significant seizure protection.Conclusion:As combined use of sodium valproate and flunarizine has shown significant seizure protection in PTZ model, flunarizine has a potential for add-on therapy in refractory cases of partial seizures. It is therefore, we conclude that further experimental studies and multicenter clinical trials involving large sample size are needed to establish flunarizine as add-on therapy in refractory epilepsy.

Anticonvulsant effect of (E)-2-benzylidene-4-phenyl-1,3-diselenole in a pilocarpine model in mice

Aim This study investigated the in vitro antioxidant activity of (E)-2-benzylidene-4-phenyl-1,3-diselenole (BPD), the anticonvulsant effect of BPD on seizures induced by pilocarpine (PC), pentylenetetrazole (PTZ) and 4-aminopyridine (4-AMP) and the mechanism involved. Methods BPD antioxidant activity in vitro was investigated using sodium nitroprusside (SNP) and malonate-induced thiobarbituric acid reactive species (TBARS) and sodium azide-induced reactive species (RS) production. Thiol peroxidase and oxidase as well as δ-aminolevulinate dehydratase (δ-ALA-D) activities were examined. Mice were pretreated via oral route (p.o.) with BPD (1–100 mg/kg) before intraperitoneal (i.p.) administration of PC (400 mg/kg), PTZ (80 mg/kg) or 4-AMP (12 mg/kg). To investigate the antioxidant effect of BPD on oxidative stress induced by PC, the activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST) and catalase (CAT) as well as the levels of RS and TBARS were determined in brains of mice. δ-ALA-D, acetylcholinesterase (AChE) and Na + , K + ATPase activities were verified. Key findings BPD (5 μM) reduced RS production and lipid peroxidation induced by SNP and malonate. BPD (1–50 μM) did not show thiol peroxidase and oxidase activities and did not alter δ-ALA-D activity. BPD (5 mg/kg) increased the latency to the seizure onset on PTZ and 4-AMP models. BPD (100 mg/kg) abolished seizures and death induced by PC in mice. BPD protected against the increase in RS and TBARS levels. The activity of Na +, K + ATPase and AChE inhibited by PC remained unaltered in the BPD group. Significance BPD showed anticonvulsant and antioxidant effects on seizures induced by PC in mice.

Halogenated aromatic amino acid 3,5-dibromo-d-tyrosine produces beneficial effects in experimental stroke and seizures

The effects of the halogenated aromatic amino acid 3,5-dibromo-D: -tyrosine (3,5-DBr-D: -Tyr) were studied in rat models of stroke and epileptic seizures caused by middle cerebral artery occlusion (MCAo) through respective intracerebral injection of endothelin-1 (ET-1) and intraperitoneal (i.p.) injection of pentylenetetrazole (PTZ). 3,5-DBr-D: -Tyr was administered as three bolus injections (30 or 90 mg/kg, i.p.) starting at 30, 90, and 180 min after ET-1 administration or as a single bolus (30 mg/kg, i.p.) 15 min prior to PTZ administration. Neurological deficits and infarct volume were estimated 3 days after ET-1 administration and seizure score was assessed during the first 20 min after PTZ administration. The safety of 3,5-DBr-D: -Tyr was evaluated in control animals using telemetry to measure cardiovascular parameters and immunostaining to assess the level of activated caspase-3. 3,5-DBr-D: -Tyr significantly improved neurological function and reduced infarct volume in the brain even when the treatment was initiated 3 h after the onset of MCAo. 3,5-DBr-D: -Tyr significantly depressed PTZ-induced seizures. 3,5-DBr-D: -Tyr did not cause significant changes in arterial blood pressure, heart rate and spontaneous locomotor activity, nor did it increase the number of activated caspase-3 positive cells in the brain. We conclude that 3,5-DBr-D: -Tyr, by alleviating the deleterious effects of MCAo and PTZ in rats with no obvious intrinsic effects on cardiovascular parameters and neurodegeneration, exhibits promising potential as a novel therapeutic direction for stroke and seizures.

Mice lacking Melanin Concentrating Hormone 1 receptor are resistant to seizures

The Melanin Concentrating Hormone (MCH) system is widely expressed throughout the central nervous system and regulates a variety of physiological functions. It has been reported that acute central administration of MCH inhibits pentylenetetrazol (PTZ)-induced seizures in rats. In the present study MCH1 receptor knockout mice (MCH1R-KO) were used to investigate the role of MCH signaling in modulating seizure susceptibility. Seizure behaviors were compared between MCH1R-KO and wild type (MCH1R-WT) mice following administration of the convulsant compounds PTZ or pilocarpine. PTZ injection induced clonic seizures in MCH1R-WT mice but failed to induce them in MCH1R-KO mice. More than twice as many injections of intermittently administered low dose PTZ were required to induce clonic seizures in MCH1R-KO mice than in MCH1R-WT mice. Following pilocarpine injection, MCH1R-WT mice experienced clonic seizures and most had tonic seizures and entered status epilepticus, while all MCH1R-KO mice were completely resistant to these effects. MCH1R-KO mice were also observed to be strongly protected from the development of PTZ kindling. Genetic deletion of MCH1R conferred resistance to all seizure models tested in this study. The data indicate that the MCH system is involved in the regulation of PTZ and pilocarpine seizure threshold.

Anticonvulsant Activity of Ethanol Leaf Extract of Spathodea campanulata P. Beauv (Bignoniaceae)

The anticonvulsant properties of ethanol leaf extract of Spathodea campanulata, a plant used in traditional medicine to treat convulsion and epilepsy, were studied in mice using pentylenetetrazole-, picrotoxin-, and electroshock-induced models in mice. Other central nervous system effects and anticonvulsant-related activities such as the effects on position sense, righting reflex, Rota-Rod performance, phenobarbital sleep time, and amphetamine-induced stereotypy were also investigated. The acute toxicity potential in mice was determined by the oral route. The results showed that the administration of S. campanulata extract (250-1,000 mg/kg, p.o.) 30 minutes prior to intraperitoneal administration of pentylenetetrazole (70 mg/kg) or picrotoxin (5 mg/kg) protected the treated mice against the respective pentylenetetrazole- and picrotoxin-induced convulsion in a dose-dependent manner, offering 100% protection at the maximum dose of 1,000 mg/kg. The extract increased the threshold of maximum electroshock and reduced duration of convulsive episodes, dose-dependently. Oral administration of S. campanulata ethanol extract did not significantly (P > .05) affect other centrally coordinated behaviors and convulsion-related properties such as position sense, righting reflex, Rota-Rod performance, phenobarbital sleep time, and amphetamine-induced stereotypy in treated animals. The oral median lethal dose of the extract was estimated as 4.5 g/kg. These results show that the ethanol leaf extracts of S. campanulata possess anticonvulsant activity. The results also show that S. campanulata extract is nonsedating, has no antipsychotic properties, and may not affect motor coordination when used as an anticonvulsant.

Acquisition of an Active Avoidance Reaction in Rats and Morphological Changes in the Hippocampus in Pentylenetetrazol Kindling

The relationship between measures of active avoidance behavior and morphological changes in the hippocampus was studied in rats after kindling induced by administration of pentylenetetrazol. Pentylenetetrazol kindling impaired the acquisition of the avoidance reaction and increased the number of intersignal reactions without altering the acquisition of the avoidance reaction in the shuttle box in rats. The numbers of neurons in the hippocampus (fields CA1 and CA3) and dentate fascia decreased, while the numbers of damaged neurons increased. Inverse correlations between seizure severity and the numbers of neurons in hippocampal fields CA1 and CA3 and the dentate fascia were seen in rats subjected to kindling. Rats of this group also showed positive correlations between seizure severity and the numbers of damaged neurons in field CA1 and the dentate fascia. There were no correlations between measures of convulsive activity or the number of cells in hippocampal zones and measures of the acquired avoidance behavior. Control animals showed negative correlations between the numbers of damaged cells in field CA1 and the dentate fascia and the characteristics of avoidance behavior in the first and third training sessions.

Time course of changes in the concentrations of monoamines in the brain structures of pentylenetetrazole-kindled rats

This work attempted to "biochemically" map the brain structures that are recruited at the different stages of pentylenetetrazole (PTZ) kindling (in a model of temporal lobe epilepsy induced by a repeated, systemic administration of PTZ, at a subconvulsive dose of 35 mg/kg). We observed substantial changes in the levels of noradrenaline (NA), 5-hydroxytryptamine (5-HT), dopamine (DA), and their metabolites in the brain structures known to be recruited in the course of kindling, i.e., the piriform, entorhinal and prefrontal cortices, and the hippocampus (in vitro). Kindling of seizures induced time-, seizure-, and structure-dependent increases in the local levels of NA, 5-HT, 5-hydroxyindolacetic acid, DA, homovanillic acid, and 3,4-dihydroxyphenylacetic acid. Surprisingly, limited changes in monoamines (NA and 5-HT) were found in the amygdala. The most potent and widespread effects concerned the serotonergic system, indicating a possible protective role of its enhanced activity in the control of the kindling of seizures. These new data indicate a pattern of changes in the basal activity of local monoaminergic innervation of brain limbic structures, accompanying the induction and propagation of seizures.

Brain uptake of diazepam and phenytoin in a genetic animal model of absence epilepsy

1. Although many studies have assessed changes to brain uptake of anti-epileptic drugs (AEDs) in chemically and electrically induced seizure models, there are limited data available on changes to brain uptake of AEDs in spontaneous seizure animal models, such as genetic absence epilepsy. 2. In the present study, the brain uptake of diazepam and phenytoin was assessed in a genetic mouse model of absence seizures harbouring a human GABA(A) receptor gamma2-subunit gene GABRG2 mutation (R43Q) and results were compared with those obtained during acute seizures induced by subcutaneous administration of pentylenetetrazole (PTZ; 90 mg/kg). Diazepam and phenytoin were administered intraperitoneally at doses of 2 and 30 mg/kg, respectively, and brain and plasma concentrations were determined 60 min after administration using liquid chromatography-mass spectrometry. 3. Although the brain uptake of phenytoin was significantly reduced following PTZ administration, no changes were observed in phenytoin disposition in the genetic absence epilepsy model. Similarly, the brain uptake of diazepam was significantly enhanced following PTZ administration, but it was not affected in absence epilepsy. 4. The cerebrovascular plasma volume (assessed by administration of the non-absorbable marker [(14)C]-inulin) was not significantly different in saline-treated compared with PTZ-treated mice and in wild-type compared with mutant R43Q mice. 5. These results demonstrate that although the brain uptake of AEDs may be altered in acute seizure models, similar changes to brain uptake may not be observed in the non-convulsive genetic absence epileptic model.

Effect of Carbamazepine and Lamotrigine on Cognitive Function and Oxidative Stress in Brain during Chemical Epileptogenesis in Rats

The present study assessed the effect of carbamazepine and lamotrigine on cognitive function and oxidative stress in brain during chemically induced epileptogenesis in rats. Epileptogenesis was induced by administration of pentylenetetrazole (30 mg/kg, s.c.) on alternate days (three times/week) for 9-11 weeks or until stage 4 of seizure score was achieved. The neurobehavioural parameters used for cognitive assessment were step-down latency in continuous avoidance apparatus and transfer latency in elevated plus maze test paradigm. Carbamazepine and lamotrigine were administered intraperitoneally in doses of 60 mg/kg and 25 mg/kg, respectively, according to the groups, once a day for 11 weeks. Oxidative stress was assessed in isolated homogenized whole brain samples and estimated for the levels of malondialdehyde, reduced glutathione, catalase and superoxide dismutase. The results showed that lamotrigine did not produce any change in cognitive function, while carbamazepine produced cognitive dysfunction. Cognitive decline seen in the carbamazepine-treated pentylenetetrazole-kindled group was also associated with increased oxidative stress. Lamotrigine treatment had no effect on oxidative stress parameters alone, while it significantly decreased oxidative stress in the pentylenetetrazole-kindled group as compared to the pentylenetetrazole-kindled carbamazepine-treated group.

Intestinal inflammation and seizure susceptibility: understanding the role of tumour necrosis factor-α in a rat model

Abstract Objectives The aim of the study was to evaluate the correlation between colitis and susceptibility to seizures. Methods Colitis was induced in Wistar rats by a single intracolonic administration of trinitrobenzene sulfonic acid (TNBS; 20 mg in 35% ethanol). The control group were given intracolonic vehicle. One group of rats with colitis were treated with thalidomide (150 mg/kg p.o.) daily for 14 days. The other colitis group received vehicle only. On day 15, seizure susceptibility was tested by administration of pentylenetetrazole (40 mg/kg i.p.). Colonic tissue was collected for estimation of morphological score, and malondialdehyde, superoxide dismutase, catalase and glutathione peroxidase. Tumour necrosis factor (TNF)-α levels were measured in serum and brain samples. Key findings The colitis group showed a significant increase in seizure score and reduction in onset time compared with the control group. Thalidomide was protective against seizures, resulting in decreased seizure score and significantly delaying the onset of seizures. Thalidomide also provided significant protection against TNBS-induced colonic damage in terms of morphological and histological score and levels of lipid peroxidation, superoxide dismutase, catalase and glutathione peroxidase in colonic tissue. The level of TNF-α in serum was also reduced significantly whereas brain TNF-α level was reduced but not significantly. Conclusions TNBS-induced colitis increased seizure susceptibility to a subconvulsive dose of pentylenetetrazole; the immunomodulator thalidomide was protective.

The effect of l-arginine and l-NAME on pentylenetetrazole induced seizures in ovariectomized rats, an in vivo study

The role of ovarian hormones and nitric oxide (NO) on seizure and their interaction have been widely investigated. The present study carried out to evaluate the effect of chronic administration of l-arginine ( lA) and l-NAME ( lN) on pentylenetetrazole (PTZ) induced epilepsy in ovariectomized (OVX) and naïve female rats. Fourty-eight female rats were randomly divided into six groups ( n = 8) as follows: (1) sham, (2) ovarectomized (OVX), (3) sham- lA, (4) sham- lN, (5) OVX- lA, and (6) OVX- lN. The animals of sham- lA and OVX- lA received daily injection of 500 mg/kg l-arginine (i.p.) during 4 weeks. Sham- lN and OVX- lN were treated by 10 mg/kg l-NAME (i.p.) daily for 4 weeks. The animals of sham and OVX groups received 1 ml/kg saline (i.p.) instead of l-arginine and l-NAME. The latencies to minimal clonic seizures (MCS) and generalized tonic–clonic seizures (GTCS) after intraperitoneal injection of penetylenetetrazole (PTZ, 90 mg/kg) was recorded and compared between groups. A significant increase in the GTCS, but not MCS, latency was seen in OVX rats in comparison with sham-operated animals. Pretreatment of animals with l-NAME resulted in a significant increase in the GTCS and MCS latencies in sham group while no significant effects were seen in OVX rats. On the contrary, while pretreatment with l-arginine had no effects on MCS and GTCS latencies in sham group, a significant decrease in GTCS latency was observed in OVX rats. It is concluded that ovarian sex hormones affect seizure thresholds induced by PTZ and NO has a role on seizures susceptibility following PTZ administration. This NO effect might be differing in the presence or absence of ovarian hormones, but further investigations need to be done.

Antiseizure effects of 3α-androstanediol and/or 17β-estradiol may involve actions at estrogen receptor β

Testosterone (T), the principal androgen secreted by the testes, can have antiseizure effects. Some of these effects may be mediated by T’s metabolites. T is metabolized to 3α-androstanediol (3α-diol). T, but not 3α-diol, binds androgen receptor. We investigated effects of 3α-diol (1 mg/kg, SC) and/or an androgen receptor blocker (flutamide 10 mg, SC), 1 hour prior to administration of pentylenetetrazol (85 mg/kg, IP). Juvenile male rats administered 3α-diol had less seizure activity than those administered vehicle. Flutamide had no effects. T is aromatized to 17β-estradiol (E 2), which, like 3α-diol, acts at estrogen receptors (ERs). Selective estrogen receptor modulators that favor ERα (propyl pyrazole triol, 17α-E 2) or ERβ (diarylpropionitrile, coumestrol, 3α-diol), or both (17β-E 2), were administered (0.1 mg/kg, SC) to juvenile male rats 1 hour before pentylenetetrazol. Estrogens with activity at ERβ, but not those selective for ERα, produced antiseizure effects. Actions at ERβ may underlie some antiseizure effects of T’s metabolites.

Intestinal inflammation and seizure susceptibility: understanding the role of tumour necrosis factor-α in a rat model

The aim of the study was to evaluate the correlation between colitis and susceptibility to seizures. Colitis was induced in Wistar rats by a single intracolonic administration of trinitrobenzene sulfonic acid (TNBS; 20 mg in 35% ethanol). The control group were given intracolonic vehicle. One group of rats with colitis were treated with thalidomide (150 mg/kg p.o.) daily for 14 days. The other colitis group received vehicle only. On day 15, seizure susceptibility was tested by administration of pentylenetetrazole (40 mg/kg i.p.). Colonic tissue was collected for estimation of morphological score, and malondialdehyde, superoxide dismutase, catalase and glutathione peroxidase. Tumour necrosis factor (TNF)-alpha levels were measured in serum and brain samples. The colitis group showed a significant increase in seizure score and reduction in onset time compared with the control group. Thalidomide was protective against seizures, resulting in decreased seizure score and significantly delaying the onset of seizures. Thalidomide also provided significant protection against TNBS-induced colonic damage in terms of morphological and histological score and levels of lipid peroxidation, superoxide dismutase, catalase and glutathione peroxidase in colonic tissue. The level of TNF-alpha in serum was also reduced significantly whereas brain TNF-alpha level was reduced but not significantly. TNBS-induced colitis increased seizure susceptibility to a subconvulsive dose of pentylenetetrazole; the immunomodulator thalidomide was protective.

A rodent model of appetitive discrimination with concomitant evaluation of anxiety-like behavior

The plus-maze discriminative avoidance paradigm has been used to study the relationship between aversive memory and anxiety. The present study aims to verify if the elevated plus-maze can provide information about appetitive memory and anxiety-like behavior, through a task motivated by food reward. Animals were allowed to explore an elevated plus-maze and received reinforcement in one of the enclosed arms. In a test session performed 24h later, in the absence of reward, rats showed preference for the previously rewarded enclosed arm over the neutral enclosed arm. The administration of diazepam and pentylenetetrazole before training induced, respectively, anxiolytic and anxiogenic effects (as evaluated by open-arm exploration). Both drugs induced amnestic effects, i.e., lack of preference for the rewarded arm in the test session. The results suggest that appetitive memory can be influenced by anxiety levels as well. The plus-maze appetitive discrimination task seems to be a useful model to investigate the relationship between memory and anxiety.

Preferential increase in the hippocampal synaptic vesicle protein 2A (SV2A) by pentylenetetrazole kindling

The present study evaluated the expressional levels of synaptic vesicle protein 2A (SV2A) and other secretary machinery proteins (i.e., soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, Munc18-1, N-ethylmaleimide-sensitive factor (NSF) and soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP)) in a pentylenetetrazole (PTZ) kindling model. Repeated administration of sub-convulsive PTZ (40 mg/kg, i.p.) progressively increased seizure susceptibility in mice and consistently induced clonic seizures in most animals tested at 15 days after the treatment. Western blot analysis revealed that, among the secretary machinery proteins examined, hippocampal SV2A was selectively elevated by PTZ kindling. PTZ kindling-induced SV2A expression appeared region-specific and the SV2A levels in the cerebral cortex or cerebellum were unaltered. In addition, SV2A expression by PTZ kindling was prominent in the hilar region of the dentate gyrus (DG) where GABAergic interneurons are located, but not in other hippocampal regions (e.g., the stratum lucidum of the CA3 and synaptic layers surrounding CA1 or CA3 pyramidal neurons). These findings suggest that PTZ kindling preferentially elevates SV2A expression in the hippocampus probably as a compensatory mechanism to activate the inhibitory neurotransmission.

Development of pentylenetetrazole kindling in rats is associated with an increase in hippocampal doublecortin expression

Doublecortin is a 50 kDa protein normally expressed in neurons at early stages of their differentiation. In this study, we investigated the doublecortin expression in rat hippocampus during chronic pentylenetetrazole administration (kindling). Rats were decapitated after the 1st, 3rd, 5th, and 13th injection of the chemoconvulsant at a subconvulsive dose; doublecortin levels were assessed using Western-blot analysis. Antibodies to doublecortin stained two proteins with molecular weights of 50 and 70 kDa. Doublecortin expression increased after 13 injections of pentylenetetrazole, which indicates intensification of neurogenesis in the hippocampus of rats with increased seizure readiness. The 70 kDa proteins were found in both neocortex and hippocampus; changes in their expression did not correlate with doublecortin expression.

Pentylenetetrazole as an unconditioned stimulus for olfactory and contextual fear conditioning in rats

The association of five footshocks with a neutral odor is able to establish an olfactory fear conditioning in rats. The present study sought to investigate whether the systemic administration of pentylenetetrazole (PTZ; 3.75–15 mg/kg) would turn the coffee odor in a conditioned stimulus in the fear conditioning paradigm. The results showed that rats started to display risk assessment and avoidance after PTZ (15 mg/kg)–coffee odor pairing. When three mild footshocks (0.4 mA for 2 s) were delivered during this pairing, the conditioned response exhibited was greater than before. In both cases, however, pretreatment with the benzodiazepine midazolam (MDZ. 0.5 mg/kg i.p.) fully counteracted the expression of these defensive behaviors. Moreover, after being paired with 15 mg/kg of PTZ alone or combined with footshocks, the coffee odor was able to promote a new fear conditioning related to the context where it was re-exposed. The present findings point out the usefulness of PTZ as an unconditioned stimulus to promote fear conditioning to olfactory and contextual cues in rats.