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Kindling induced by the convulsant pentylenetetrazol (PTZ) is an accepted model of primary generalized epilepsy. Because seizures represent a strong distressing stimulus, stress-induced proteins such as heat shock proteins might counteract the pathology of increased neuronal excitation. Therefore, the aim of the present study was to determine whether PTZ kindling outcome parameters are influenced by heat shock protein 70 (Hsp70) overexpression in Hsp70 transgenic mice as compared to the respective wild-type mice. Kindling was performed by nine intraperitoneal injections of PTZ (ED(16) for induction of clonic-tonic seizures, every 48 h); control animals received saline instead of PTZ. Seven days after the final injection, all mice received a PTZ challenge dose. Outcome parameters included evaluation of seizure stages and overall survival rates. In addition, histopathological findings such as cell number in hippocampal subfields CA1 and CA3 were determined. The onset of the highest convulsion stage was delayed in Hsp70 transgenic mice as compared to wild-type mice, and overall survival during kindling was improved in Hsp70 transgenic mice as compared to wild-type mice. In addition, a challenge dose after termination of kindling produced less severe seizures in Hsp70 transgenic mice than in wild-type mice. PTZ kindling did not result in significant subsequent neuronal cell loss in CA1 or CA3 neither in wild-type mice nor in the Hsp70 transgenic mice. The results of the present experiments clearly demonstrate that overexpression of Hsp70 exerts protective effects regarding seizure severity and overall survival during PTZ kindling. In addition, the decreased seizure severity in Hsp70 transgenic mice after a challenge dose suggests an interference of Hsp70 with the developmental component of kindling.

Purpose: The aim of the study was to define sleep disturbances in pentylenetetrazole (PTZ)-kindled rats and to explore the effects of the nootropic drug piracetam (Pir; 100 mg/kg) and the noncompetitive N-methyl-D-aspartate (NMDA)-antagonist MK-801 (0.3 mg/kg), which normalized learning performance in PTZ-kindled rats, on altered sleep parameters., Methods: This is the first report showing a significant reduction in paradoxical sleep (PS) as a consequence of PTZ kindling. A correlation analysis revealed a significant correlation between seizure severity and PS deficit., Results: Pir did not interfere with seizure severity, and the substance did not ameliorate the PS deficit. However, the substance disconnected the correlation between seizure severity and PS deficit. MK-801, which reduced the severity of kindled seizures, counteracted the PS deficit efficaciously., Conclusions: The results suggest that seizure severity and alterations in sleep architecture are two factors in the comprehensive network underlying learning impairments associated with epilepsy. Considering the results obtained in the experiments with Pir, reduction of seizure severity does not guarantee the reduction of impairments in the domain of learning.

Brailowsky and Garcia (1999) proposed the existence of a relationship between epilepsy and addiction. To prove this hypothesis, pentylenetetrazol kindled rats were tested in the conditioned place preference (CPP) paradigm for their reaction to various addictive drugs with different modes of action (morphine, cocaine and ethanol). In separate experiments, locomotor activity and body temperature after application of the same drugs were tested in kindled and non-kindled rats. In the CPP experiment there were significant differences between both groups of rats. Non-kindled animals showed place preference to morphine (5.0 mg/kg) or cocaine (20.0 mg/kg). This reaction was abolished in the kindled rats. Moreover, control rats demonstrated aversion to 2.0 g/kg ethanol. However, ethanol aversion was not detectable in kindled rats. Moreover, there was no difference between non-kindled and kindled rats in locomotor activity and body temperature after morphine (1.0 and 5.0 mg/kg), cocaine (10.0 and 20.0 mg/kg), or ethanol (0.5 and 2.0 g/kg) application. This suggests alterations in reward systems as a consequence of kindling. It is hypothesised that GABAergic neurones in the ventral tegmental area might play a major role in the alterations found.

LY 367385 (mGluR1) and MPEP (mGluR5), which are group I metabotropic glutamate receptor (mGluR) antagonists, were used to investigate their effects on pentylenetetrazole (PTZ) seizures, kindling, and kindling-related learning deficits. Both substances showed anticonvulsant efficacy against seizures induced by lower doses of PTZ (40 mg/kg), but they were ineffective in counteracting seizures evoked by higher PTZ doses. When these substances were given in the course of kindling induction, LY significantly depressed the progression of kindled seizure severity. In contrast, MPEP was ineffective in this experiment. Treatment with either LY or MPEP did not modify the reaction to challenge dose of PTZ. Kindling results in a worsening of shuttle-box learning. LY improved shuttle-box learning when administered in the course of kindling development or when given prior to the learning experiment. This suggests protective and restorative effectiveness. In contrast, MPEP was only effective on the learning performance of kindled rats when given prior to the shuttle-box experiment, which demonstrates restorative effectiveness. Kindling is associated with an increase in glutamate binding. LY counteracted this increase whereas MPEP was ineffective. It was concluded that mGluR1 and mGluR5 play a specific role in the convulsive component of kindling. The beneficial action of the antagonists on kindling-induced impairments in shuttle-box learning may be associated with their effect on glutamatergic synaptic activity.

The relevance of mu-opioid systems for central excitability and kindling related disturbed learning performance was underlined by investigations using mu-opioid receptor knockout mice. Mice lacking mu-opioid receptors showed an accelerated kindling development induced by the convulsant drug pentylenetetrazol. Blockade of delta-opioid receptors by naltrindole suppressing kindling development in wild-type animals led to a further acceleration of kindled seizure development in the knockout mice. Mice lacking mu-opioid receptors showed such a low learning performance in the shuttle box, that the kindling induced learning deficit as seen in wild-type mice was not detected. The results were discussed on the basis of receptor binding studies with regard to subtypes of glutamatergic receptors, delta-opioid and somatostatin receptors. An increase in glutamate and somatostatin binding could contribute to the enhanced excitability in the-mu-opioid receptor knockout mice.

Kindled seizures are widely used as a model for epileptogenesis. Although the achievement of kindling criterion is known to require time to develop, the precise developmental period has not been identified. We now report that optimal achievement of the kindling criterion in the Sprague-Dawley rat is associated with a critical inter-stimulus interval of 24 to 26 days. We show that highly efficient kindling can be achieved with only two subconvulsive doses of pentylenetetrazole so long as they are given 25 days apart. Using Northern blot hybridization we show that the increased seizure susceptibility at 25 days coincides with an increased expression of the plasticity-associated proteins, growth-associated protein-43 (GAP-43), microtubule-associated protein 1B (MAP1B), and tissue plasminogen activator (tPA) mRNAs in the hippocampus. By in situ hybridization and immunocytochemistry on tissue sections, we also show an increased expression for GAP-43 in the polymorphic layer of the dentate gyrus, mossy fibers, and pyramidal cells in the CA3 region of the hippocampus. The demonstration of a long, defined developmental interval for inducing the kindling criterion should enable a dissection of the cellular and genetic events underlying this phenomenon in the rat.

The present work analyzed the changes in evoked field potentials of freely moving rats after kindling induced by a convulsant inverse agonist of the GABA(A)-benzodiazepine receptor complex, methyl beta-carboline-3-carboxylate (beta-CCM). Two doses of beta-CCM (2 mg/kg and 4 mg/kg) were used. In kindled and control animals, a stimulating electrode was implanted in the perforant pathway and a recording electrode in the dentate gyrus. Results showed that, after an acutely injected dose of 20 mg/kg pentylenetetrazol (PTZ), all kindled animals showed a decrease in population spike amplitude after 20 min. After 60 min, only fully kindled rats showed a long-lasting potentiation, also visible up to 24 h later, as compared to controls or nonkindled animals. Changes in glutamate and GABA receptor binding measured in previous experiments may explain this potentiation effect observed in fully kindled rats.

In the present study kindling was induced in rats by repeated intraperitoneal injection of pentylenetetrazol (PTZ) once every 48 h. The resulting seizure stages were registered after each PTZ application. The development of PTZ-induced kindling and the time course of possible potentiation effects in the dentate gyrus were examined. The efficacy of perforant pathway transmission to the granule cells was tested in every second kindling session by measuring the monosynaptic evoked field potentials recorded in the dentate gyrus following single test stimuli of the perforant pathway at different times after PTZ injection in freely moving animals. The data suggest that establishment of a PTZ kindling is associated with the development of long-lasting potentiation of the field potentials. After completion of kindling it was demonstrated that kindled rats also show a diminished learning performance. The relationship between the development of potentiation phenomena in hippocampal substructures and learning impairment is discussed.

Kindling, recognized as a model of epilepsy, can be obtained by applications of repeated nonconvulsive stimulations that finally lead to generalized seizures. Epileptics often show cognitive impairments. The present work analyzed the learning performance of male Wistar rats kindled with a convulsant inverse agonist of the GABA(A)-benzodiazepine receptor complex, methyl beta-carboline-3-carboxylate (beta-CCM). This compound is also known to have an action on learning processes. It was thus interesting to verify if beta-CCM kindling had the same impairing action on learning as other kindling agents, such as pentylenetetrazol (PTZ). A two-way active-avoidance shuttle-box learning task was chosen, because a deficit was found after PTZ kindling in this learning model. On the other hand, hippocampal glutamate binding, has previously been shown to be modified by both seizures and learning. Thus, the level of glutamate binding was also measured in the present study. Results showed that fully kindled rats had poorer learning performance after the third day of test than controls or not fully kindled animals. L-[3H] glutamate binding to hippocampal membrane fractions of the fully kindled animals was significantly higher when compared with controls, whereas L-[3H] glutamate binding of not fully kindled subjects did not differ from that of controls. Neuronal plasticity changes are a possible explanation for the correlation between kindling, learning deficits, and increased glutamate binding.

Kindling-induced activation of dopaminergic neurones in the nucleus accumbens in pentylenetetrazol (PTZ)-kindled rats was studied using microdialysis. Dopamine (DA) release after PTZ challenge was measured: (1) two weeks and (2) ten weeks after kindling completion and (3) two weeks after a kindling procedure with diazepam (DZP) treatment. In (1) a significant increase in DA concentration was found after PTZ challenge and this increase was still evident 10 weeks after kindling completion (2). Coadministration of DZP in the course of kindling development inhibited the increase in sensitivity of the accumbens dopaminergic system (3).

Kindling is considered to be a useful experimental model for investigating drug effects on the convulsive component of epilepsy and related alterations at the behavioural level. It was demonstrated that pentylenetetrazol (PTZ)-kindled rats show diminished learning performance in shuttle-box training. We used this model to study the influence of nicardipine, an antagonist of L-type voltage-dependent calcium channels, on kindling seizure development as well as related learning impairments. Additionally, we tested the influence of nicardipine on kindling-induced potentiation, a special form of long-term enhancement of evoked potentials in the dentate gyrus after kindling. Therefore, monosynaptic evoked field potentials in the dentate area upon test stimuli to the perforant pathway were recorded in freely moving kindled and control rats at different times after injection of PTZ. The results indicate that the blockade of L-type voltage-dependent Ca2+-channels during the kindling procedure attenuates PTZ-kindling, antagonizes a kindling-induced learning deficit in an active avoidance test and decreases a novel form of kindling-related potentiation, the long-lasting amplitude enhancement of the monosynaptic evoked field potential in the dentate gyrus after injection of a small test dose of PTZ. This potentiation can also be prevented in kindled animals by nicardipine injection in an acute experiment.

Kindling is a generally accepted model for studying epilepsy development in the context of overexpression of processes of neuronal plasticity. In previous studies we have shown that establishment of kindling by repeated application of subconvulsive doses of pentylenetetrazol (PTZ) also led to marked changes in hippocampal excitability and an impairment in learning behaviour. With the intention of further investigating the relationship between kindling development, kindling-induced changes in excitability and learning deficits, rats were chemically kindled under pretreatment with the nootropic drug piracetam. Furthermore, we tested acute piracetam effects on developed kindling seizures, the learning deficit and potentiation effects. At the investigated dose piracetam did not influence the kindling development. The kindling-induced potentiation of hippocampal field potentials was significantly diminished in piracetam-pretreated rats. Piracetam acutely injected completely antagonized this potentiation effect. Piracetam brought about a significant improvement in impaired learning performance in rats pretreated during kindling induction and acutely injected before the learning experiment, respectively. Possible correlations between the suppressing of the kindling related potentiation in hippocampal structures by piracetam and its beneficial effect on learning impairment are discussed as antagonizing overexpression of potentiation in the course of kindling.

The role of delta-opioid receptors on the development of kindling induced by the convulsant pentylenetetrazol (37.5 mg kg(-1) i.p.) was investigated in rats. Besides the seizure development, the kindling induced enhancement of glutamate binding and the kindling-induced learning deficit were examined. A clear depression of kindling development by blocking of delta-opioid receptors by intracerebroventricular administration of naltrindole (10 nmol/5 microl) was found. In an acute convulsion test performed 8 days after kindling completion, animals pretreated with naltrindole during kindling induction showed lower seizure stages compared to saline-pretreated kindled animals. The kindling-induced increase in hippocampal glutamate binding was completely prevented by naltrindole, whereas the kindling-induced learning deficit was not influenced. The learning performance of control animals pretreated with naltrindole was very low. It was hypothesized that the various consequences of kindling induction could be influenced separately. Summarizing the results, an involvement of the delta-opioid system in mechanisms underlying chemical kindling was clearly demonstrated. Interactions of endogenous opioid systems with glutamatergic transmission were suggested.

Opioids are involved in the development of epileptic seizures. Recently, interest has been focused on the role of the kappa-opioid receptor agonists as novel approaches to the treatment of epilepsy. In the present study we investigated the effects of the kappa-opioid receptor agonist enadoline (Ena) on pentylenetetrazol (PTZ) induced seizures, PTZ kindling, shuttle-box performance and hippocampal neuromorphology. Ena injected i.c.v. in doses of 1 and 10 nmol did not affect acute PTZ seizures. In the course of PTZ kindling development, co-treatment (1 nmol) with the kappa-opioid receptor agonist suppressed seizure strength. Eight days after kindling completion the animals received a challenge dose of PTZ. In reaction to challenge, kindled animals which were pretreated with Ena reached significantly lower seizure scores. Kindling resulted in diminished shuttle-box performance. Learning performance in kindled animals pretreated with Ena was not normalised. Kindling resulted in increased glutamate binding. Interestingly, in comparison with the saline/saline group, neither in the Ena/saline nor in the Ena/PTZ treated groups changes in glutamate binding were found. That means that Ena prevented the increase in glutamate binding in the kindled group. In kindled animals significant cell loss in CA1 of the dorsal hippocampus was found and this was efficaciously counteracted by Ena. However, Ena alone did induce similar cell loss compared to kindled animals. It is hypothesised that the effects of enadoline are mainly due to interferences with glutamatergic systems., (Copyright 1999 Elsevier Science B.V.)

Endogenous opioids modulate processes of central excitability such as long-term potentiation and electrical kindling. Little is known about the neurochemical alterations in the interaction of the glutamatergic and opioid system in the development of pentylenetetrazol (PTZ) kindling in rats. Therefore, in the present study we investigated glutamate, DAMGO and naltrindole receptor binding, receptor protein expression by Western blot and ex vivo glutamate transmitter release in PTZ kindled rats. The specific 3H-DAMGO and -naltrindole binding to hippocampal membranes displayed no significant changes in kindled rats compared to controls. In contrast, the 3H-l-glutamate binding was significantly enhanced after completion of PTZ kindling. The expression of receptor protein for glutamate as well as the naloxone- and naltrindole-induced 3H-d-aspartate release from hippocampal slices did not alter in any case as a consequence of PTZ kindling. The PTZ induced enhancement of the glutamate binding sites in the hippocampus was downregulated to control level by natrindole treatment of rats prior to each PTZ application. Furthermore, naltrindole pretreatment of rats significantly inhibited the development of seizure susceptibility. In contrast, naloxone was not able to alter the seizure activity induced by PTZ as well as the transmitter receptor binding. The results are discussed in the light of a modulating role of delta-opioid receptors in PTZ kindling., (Copyright 1998 Elsevier Science B.V.)

Drugs with anticonvulsive properties and different mechanisms of action were compared for their influence on long-term potentiation and pentylenetetrazol kindling in freely moving animals. Rats were chronically implanted with a stimulation electrode in the angular bundle and a recording electrode in the dentate gyrus. Field potentials in the dentate gyrus were elicited and long-term potentiation was induced by stimulation of the perforant pathway. The clinically used drugs or the potentially anticonvulsive drugs, diphenylhydantoin (50 mg/kg), diazepam (0.5 mg/kg), pentobarbital (10 mg/kg), dizocilpine (MK 801, 0.2 mg/kg) and CGP 43487 (2-amino-4-methyl-5-phosphono-3-pentenoic acid-carboxyethylester, 10 mg/kg), were injected before tetanization. In behavioural experiments pentylenetetrazol kindling was performed with pretreatment with the substances in dosages indicated above (except MK 801, 0.3 mg/kg). Field potentials recorded in the interval between drug administration and tetanization were influenced only by diphenylhydantoin which enhanced the population spike amplitude to 128% of control values. However, the substances showed different effects on long-term potentiation. MK 801, CGP 43487 and pentobarbital depressed potentiation; diazepam was without effect. Diphenylhydantoin had a minor influence on induction but significantly impaired maintenance of long-term potentiation. Furthermore, MK 801, CGP 43487, diazepam and pentobarbital differentially depressed kindling whereas phenytoin only slightly influenced it. The consequences as to hypothetical common cellular mechanisms for kindling development and long-term potentiation are discussed.

Rats were kindled by repeated injections of pentylenetetrazole (PTZ; 37.5 mg/kg; i.p.) in the presence or absence of the opioid receptor antagonist naloxone. Naloxone (10 mg/kg; i.p.) applied 30 min before each PTZ application had no major effect on the seizure development, although a slight decrease in the seizure expression of fully kindled animals could be observed. In the kindled animals, a pronounced but transient increase in c-fos mRNA level was observed in several brain areas after the injection of PTZ. The magnitude of c-fos induction was related to the seizure stage reached. Detectable c-fos mRNA levels in the cortex were observed in rats showing stage four seizures, whereas the expression of c-fos in the hippocampus required stage five kindled seizures. The induction of c-fos expression in the hippocampus of stage five kindled rats but not in other brain areas was prevented by treatment of naloxone prior to each PTZ application. In contrast, a single injection of naloxone to kindled rats was not sufficient to prevent c-fos mRNA expression in the hippocampus. In addition, a single PTZ application (at the higher dose of 45 mg/kg) to rats that were not kindled also caused c-fos expression in several brain regions, but this was not influenced by naloxone. Assuming that c-fos expression reflects neuronal activity our findings suggest a functional role of endogenous opioid peptides in the development of kindling-induced neuronal excitation in the hippocampus. In addition, the excitation of the hippocampus does not appear to be involved in the seizure activity but may be responsible for the impairment of learning in PTZ-kindled rats which can be prevented by pretreatment with naloxone [A. Becker, G. Grecksch, M. Brosz, Naloxone ameliorates the learning deficit induced by pentylenetetrazole kindling in rats, Eur. J. Neurosci. 6 (1994) 1512-1515]., (Copyright 1998 Elsevier Science B. V.)

The effect of the nootropic drug piracetam (100 mg/kg) on kindled seizures, kindling-induced learning deficits, and histological alterations due to changes in central excitability was investigated in Wistar rats. The animals were kindled by repeated i.p. injections of an initially subconvulsive dose of pentylenetetrazol (PTZ). As a control, piracetam or physiological saline was given 60 minutes before PTZ. Twenty-four hours after completion of kindling the rats were tested in a shuttle-box paradigm. Seven days after the final kindling injection, the animals received a challenge dose of PTZ. Finally, the brains of the rats were processed for histological investigation. Pentylenetetrazol-kindled animals showed increasing seizure scores, and a learning deficit in the shuttle-box. Piracetam had no effect either on kindling development or on the reaction to a challenge dose of PTZ, but it protected the animals against the kindling-induced reduction of learning performance. The substance had no effect on learning performance in control animals. In distinct hippocampal structures, a neuronal cell loss was found in kindled rats. Interestingly, piracetam counteracted this damage efficaciously. The effects of piracetam are discussed in terms of its cytoprotective action. It is suggested that a coadministration of piracetam with clinically used antiepileptic drugs might be useful in antiepileptic therapy.

The hippocampus represents a heterogeneous structure which has been associated with different functions. It has been suggested that it plays an important role in both learning and memory and epileptogenesis. Thus, it is not surprising that seizure activity generated in the hippocampal formation interferes with memory storage. Little is known about the functional differentiation between the dorsal (DH) and ventral hippocampus (VH). To study this functional differentiation, we kindled Wistar rats either in the DH or in the VH by electrical stimulation. Afterwards, learning performance of these rats was tested in three different models, i.e., response to change (short-term memory), shuttle box (two-way active avoidance), and Y-chamber (brightness discrimination reaction). It was found that VH-kindled rats reached higher seizure scores than DH-kindled rats, but there was no difference in seizure duration. Kindling induced in the VH significantly impaired shuttle box learning, whereas DH-kindled rats showed a dramatically worsened acquisition in the brightness discrimination task. Different anatomical projections probably account, in part, for these differences.

The present study describes changes of response enhancement of hippocampal field potentials in slices of kindled rats using different methods to induce long-lasting potentiation. Eight-week-old male Wistar rats were subjected to pentylenetetrazol (PTZ) kindling induced by intraperitoneal injection of 45 mg/kg once every 48 h until the occurrence of seizure stages 4-5. Eight to 12 days after the last kindling session, transverse hippocampus slices were prepared and maintained in an artificial medium. Evoked-field potentials were recorded in the CA1 region upon stimulation of the Schaffer collaterals. Potentiation was induced: 1. By moderate tetanic stimulation of the Schaffer collaterals, 2. by changing the perfusion medium to 0-magnesium for 30 min, and 3. by changing the medium to 4 mM Ca2+ for 7 min. In slices from kindled rats, long-term potentiation (LTP) after tetanic stimulation and increase of the evoked potential by 0-magnesium were significantly enhanced in comparison to slices from sham-kindled rats. However, Ca(2+)-induced LTP could not be induced in slices from kindled rats. The results support the assumption that PTZ kindling also induces lasting changes in the responsiveness of hippocampal structures, expressed as an enhanced ability to induce potentiation. An alteration of N-methyl-D-aspartate (NMDA) receptor-coupled processes can be assumed. The inability to induce Ca(2+)-induced LTP points to more complex effects of PTZ, perhaps also on nonNMDA coupled ionic channels.

Epileptogenesis during ontogeny may not be linearly related to time. It is known that the behavioral manifestations of seizures are age-dependent, but more research is needed to clarify ontogenetic aspects of epilepsies and related alterations, including cognitive deficits. Kindling is an accepted animal model for the study of the convulsive component of epilepsy and its consequences on behavior. Recently, we demonstrated an impairment in acquisition of a conditioned reaction in young adult kindled rats, using pentylenetetrazol (PTZ) as the kindling stimulus. The present study was undertaken to investigate the dependence on age of alterations in the induction of PTZ kindling in rats. We started the kindling protocol in 4-, 6-, and 8-week- and 6-, 12-, 18-, and 24-month-old rats. The PTZ kindling showed an age-dependent decrease in expression of convulsions. The diminished kindling capacity was already seen in 6-month-old rats. In contrast, kindling-related impairment effects on cognitive functions increased with age. Thus, the correlation between learning impairment and occurrence of tonic-clonic seizures that we had demonstrated in 8-week-old rats was abolished in older rats. On the other hand, when the kindling procedure was started in 6-week-old rats, no impairment was found in fully kindled rats.

The study examines changes in the function of perforant pathway dentate granule cell synapses after pentylenetetrazol (PTZ) kindling. Field potentials evoked in the dentate area by test stimuli to the perforant pathway were recorded in freely moving rats at different times after injection of PTZ. In fully kindled animals, but not in sham-kindled controls, subconvulsive test doses of PTZ induced long-lasting potentiation of the population spike. Also, potentiation was not induced in naive controls injected with equieffective doses of the convulsant. The slope function of the field EPSP was depressed 90-120 min after PTZ administration, in both kindled and control animals, indicating that this was an effect of acute-injected PTZ. Later on, only in kindled animals that showed seizure stages 4 or 5 did it increase in parallel with the population spike potentiation. Finally, when compared to controls the kindled animals showed a greater pop spike potentiation induced by moderate tetanization of the perforant pathway. The model offers the possibility of differentiating between acute effects of the convulsant drug and kindling-related changes in neuronal plasticity.

Epileptics are often faced with impaired intellectual processes. The basis of these impairments is still poorly understood. Kindling is an accepted model for the study of the convulsive component of epilepsy. Furthermore, it was demonstrated that pentylenetetrazol-kindled rats show diminished shuttle-box learning. Therefore, we used this model to study the influence of flunarizine, a calcium antagonist, on kindled seizures as well as related learning impairments. It was found, that acutely administered flunarizine significantly suppressed the expression of kindled seizures, but there was no effect on the developmental character of kindling. Moreover, the substance had an anticonvulsant action when administered after completion of kindling. The learning ability of kindled rats was significantly augmented when flunarizine was injected prior to each convulsive stimulation or when administered after completion of kindling. The results were explained in terms of interactions of a depressive effect on abnormal neuronal excitation, a protection against calcium-induced neurotoxicity and, finally, the vascular effect of flunarizine.

Many epileptic patients suffer from cognitive impairments. These impairments may be a consequence of the epileptogenic process and/or antiepileptic medication. Kindling is considered a useful experimental model to investigate drug effects on both the convulsive component of epilepsy and related alterations at the behavioral level. In our experiments, kindling was induced by repeated injections of pentylenetetrazol (PTZ). To test the effect of antiepileptic drugs on kindled seizures and kindling-induced learning deficits we injected ethosuximide, dipropylacetate, and phenobarbital prior to each kindling stimulation or after kindling completion, and tested these animals in a shuttle-box paradigm. Dipropylacetate and phenobarbital suppressed the development of motor seizures and counteracted the learning deficit. Although ethosuximide had a clear effect on kindled seizures, the learning deficit occurred in kindled rats. This suggests that AEDs effects on kindled seizures are not correlated with the elimination of deficits in the field of cognition.

Pentylenetetrazol (PTZ)-kindling represents a model of a primarily generalized epilepsy. We investigated the role of the dentate gyrus of the hippocampus in this model of epilepsy by destruction of this structure by colchicine, injected in the dorsal and ventral hippocampus of rats. After a period of 7 days PTZ-kindling was started. The kindling development was slightly accelerated in colchicine treated animals compared to control rats. After kindling completion the learning performance of the rats was tested in a shuttle-box experiment. The learning deficit found in fully kindled rats was not influenced by colchicine pretreatment. However, colchicine itself impaired the learning performance of rats in the shuttle-box.

Kindling represents an accepted model of human epileptogenesis. Furthermore, it has been demonstrated that kindled rats show a diminished learning performance in an active avoidance task. In our study we administered different nootropic drugs to kindled rats to test their effects on learning a two-way active avoidance task in the shuttle-box. Kindling was induced by repeated intraperitoneal injections of 45 mg kg-1 pentylenetetrazol (PTZ) once every 48 h. The substances vinpocetine (0.1 and 1.0 mg kg-1), methylglucamin orotate (225 and 450 mg kg-1), piracetam (100 mg kg-1), and meclofenoxate (100 mg kg-1) were administered during kindling development and after kindling completion prior to each session in the learning experiment. The nootropic drugs had little if any effect on severity of seizures. Concerning their effect on learning the substances each acted in a specific manner. Methylglucamin orotate enhanced the learning deficit induced by kindling. Meclofenoxate injected prior to the kindling stimulation was ineffective, whereas administration prior to the learning test improved the learning performance effectively. A complementary action was shown in experiments with vinpocetine. Only piracetam prevented the occurrence of kindling-induced learning deficits regardless the administration schedule.

The effects of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, on seizure development and processes of glutamate neurotransmission were studied in the pentylenetetrazol (PTZ)-kindled rats. For this purpose, a dose of 10 mg/kg L-NAME was injected prior to the 13 kindling stimulations. Eight days after the final injection, glutamate binding to brain membranes was measured. It was shown that L-NAME suppressed the kindling development significantly. Furthermore, L-NAME-pretreated rats showed lower seizure scores in reaction to a challenge dose of PTZ. However, glutamate binding was not changed by the pretreatment. The data suggest an involvement of NO in the mechanisms related with kindling.

Endogenous opioid peptides modulate and regulate processes of central excitability. Furthermore, opioids are thought to interfere with processes of learning and memory storage. In order to study the effects of endogenous opioids on both processes we injected in the course of development of pentylenetetrazol kindling the opiate receptor antagonist naloxone, and tested the animals afterwards in a shuttle-box task. It was found that naloxone pretreatment had dissociative effects. There was no effect on seizure outcome, whereas the learning deficit was ameliorated in the kindled group. The data suggest that endogenous opioid peptides contribute to the learning deficit found in pentylenetetrazol-kindled rats.

Repeated administration of pentylenetetrazol (PTZ) induces kindling and impairs shuttle-box learning. The available literature suggesting a close connection between seizure frequency and mental deficits in human epileptics allows us to hypothesize that seizure inhibition prevents the progressive mental retardation associated with kindling. In order to investigate the effect of motor seizure inhibition on mental impairment we administered diazepam (DZP) doses of 0.5 and 2.5 mg/kg, respectively 60 min prior to the 10 convulsant injections. After completion of kindling the learning performance of the rats was tested in the shuttle-box. PTZ kindling resulted in diminished shuttle-box learning. In control rats treated with DZP no significant changes in their learning ability occurred. Although DZP was found to suppress kindling development effectively a worsened shuttle-box learning could be observed in all PTZ groups treated with DZP.

In amygdala-kindled rats a deficit in learning brightness discrimination was found. We concluded that this result provides a reliable basis for creating an animal model of cognitive dysfunctions in epileptics. Recently, a des-tyrosine D-amino acid substituted derivative of bovine beta-casein(1-5) was reported to exhibit anticonvulsant as well as antidepressant activity. Therefore, we tested the effect of this peptide on kindled seizures and the learning deficit after kindling. It was found that the peptide suppressed the duration of seizures whereas seizure severity was not influenced. Furthermore, the learning performance of peptide-treated rats was significantly higher than that of kindled controls.

To study the learning performance of pentylenetetrazol- and amygdala-kindled Wistar rats we used the following learning tests: short-term memory was tested in the response-to-change model, brightness discrimination was tested in a Y-chamber, and two-way active avoidance learning was tested in a shuttle-box. Short-term memory was not impaired by both kindling procedures. Considering two-way active avoidance learning the performance of pentylenetetrazol (PTZ)-kindled rats was significantly diminished. This effect persists over a period of 4 weeks. However, amygdala (AMY)-kindled rats acquired this task like the controls. In brightness discrimination reaction (BDR) the learning performance of PTZ-kindled animals was not influenced. Although the acquisition of BDR was nearly identical, the 24-h retention was remarkably diminished in AMY-kindled rats. It was hypothesized that the different kindling procedures interfere in different ways and extent with neuronal circuits resulting in different functional impairments.

Epileptic patients often show impairments in a number of cognitive functions. Kindling is considered to be a useful experimental model for human epilepsy. Recently we have demonstrated a learning impairment in a shuttle box experiment in pentylenetetrazol (PTZ)-kindled rats. This model offers the possibility to investigate the relation between repeated convulsions and their consequences on learning and on the other side to test the effectiveness of substances on both processes. Although systemic application of gangliosides has neither an effect on the development of seizures induced by repeated injections of PTZ, nor on seizures induced by PTZ in kindled animals, the treatment protects against the memory-impairing effect of convulsions. These findings suggest a new useful strategy in the therapy of epileptic patients with the aim of diminishing the psychosocial problems in persons with seizure disorders: a combination of the anticonvulsive basic therapy and gangliosides.

Some of the Tyr-containing and desTyr beta-casomorphin derivatives were tested for their anticonvulsant action in pentylenetatrazol-kindled mice. It was demonstrated that some of these substances exert powerful action against kindled seizures, suggesting therapeutical usefulness.

The activity of NADPH-diaphorase in rat telencephalic structures has been revealed by use of a histochemical method. Multiple neurons belonging to different nuclei were found to contain the enzyme. Furthermore, diaphorase reactive nerve fibres and terminal fields were observed to be widely distributed throughout rat brain. Chemical kindling induced by pentylenetetrazol (PTZ) did not effect the regional distribution and cellular localization of the enzyme in the rat CNS.

The convulsant effect of different doses of picrotoxin was investigated in pentylenetetrazol-kindled and saline-treated mice. The percentage of convulsions was greater in the kindled mice, compared to controls.