The anticonvulsant effects of diazepam and phenobarbital in prekindled and kindled seizures in rats

The effects of various doses of diazepam (0.5–4 mg/kg) and phenobarbital (7.5–60 mg/kg) were determined on prekindled and kindled amygdaloid seizures in the same rats. Diazepam was ineffective against the prekindled focal seizures, but demonstrated profound and statistically significant control of the kindled seizures. In the kindled state, diazepam reduced the afterdischarge duration and seizure rank score to prekindled levels. Only the largest sedating dose of phenobarbital produced a reduction of both prekindled afterdischarge duration and seizure rank score. Against the kindled seizure, phenobarbital showed a marked and statistically significant increase in effectiveness in all but the smallest dose tested. The afterdischarge duration of kindled seizures was reduced to prekindled levels by 15–60 mg/kg of phenobarbital, while seizure rank score was reduced to prekindled levels by 30 and 60 mg/kg phenobarbital. The effects of two doses of diazepam (0.5 and 2.5 mg/kg) and phenobarbital (7.5 and 30 mg/kg) were tested against prekindled and kindled pentylenetetrazol (PTZ)-induced seizures. Preliminary work with 3 doses of pentylenetetrazol (30, 40 and 60 mg/kg) demonstrated that repeated doses of 30 mg/kg readily kindled seizures without the significant mortality seen with larger doses. Both diazepam and phenobarbital were less effective against seizures kindled with 30 mg/kg pentylenetetrazol compared to prekindled seizures. The comparative lack of effect that was seen with diazepam and phenobarbital against the pentylenetetrazol kindled seizure at doses associated with control of the kindled amygdaloid seizure may reflect an underlying difference in the pathogenesis of kindling between these seizure models. Further, the lack of suppression of the prekindled amygdaloid afterdischarge duration by large doses of diazepam, in contrast to large doses of phenobarbital, may also reflect differences between the mechanisms of action of these two drugs. This paradigm provides a model for testing the effectiveness of anticonvulsants during the progressive development of various epileptogenic seizures.     

The effects of pentylenetetrazol, bicuculline and strychnine on the development of kindled seizures

Modification of the rate of acquisition of the kindled amygdaloid seizure by the convulsants pentylenetetrazol, bicuculline and strychnine was studied. Injections of saline, 25 mg/kg of pentylenetetrazol, 2 mg/kg of bicuculline or 1 mg/kg of strychnine were given 15 min prior to the daily electrical stimulation of the amygdala. The drug doses selected were capable of producing some behavioral and electrical epileptoid activity prior to stimulation without inducing generalized seizures. To determine whether pentylenetetrazol or bicuculline accelerated the rate of development of the kindled amygdaloid seizure or merely augmented the expression of each seizure, a crossover design was implemented. The crossover studies involved switching animals during the acquisition phase (between stimulations 3–6) from prestimulation saline to drug or drug to saline injections. It was found that pentylenetetrazol markedly augmented the expression of seizures during kindling development but the results of the crossover studies showed a less dramatic acceleration in the actual rate of the development of the fully generalized kindled amygdaloid seizure. The bicuculline-treated animals showed little augmentation in the expression of seizures during the kindling acquisition phase and in the actual rate of development of the kindled amygdaloid seizure. The strychnine treated animals showed no augmentation in expression of the seizures nor in the rate of development. The effects of prestimulation injections of bicuculline (1, 2 and 3 mg/kg) and strychnine (0.5, 1 and 2 mg/kg) on fully developed kindled amygdaloid seizures were also evaluated. Pretreatment with bicuculline minimally increased seizure afterdischarge duration at the highest dose. When fully kindled animals were pretreated with strychnine, a paradoxical decrease in afterdischarge length and an increase in severity (tonic hindlimb extension) was seen with the largest dose tested. This study emphasizes the potential importance of crossover studies in evaluating pharmacological manipulations of the rate of acquisition of the kindled seizure.     

The anticonvulsant effects of diazepam and phenobarbital in prek1ndled and kindled cortical seizures

The effects of various doses of diazepam (0.5–4 mg/kg) and phenobarbital (15–60 mg/kg) were determined on prekindled (focal) and kindled (generalized) cortical seizures in the same rats. Only high sedating doses of diazepam or phenobarbital reduced the elicited afterdischarge duration (ADD) and behavioral response in the prekindled focal cortical seizure. Against the kindled seizure, both diazepam and phenobarbital showed a marked and statistically significant increase in effectiveness in all but the smallest doses tested. The ADD of the kindled cortical seizures was reduced to prekindled lengths by diazepam (1–4 mg/kg) or phenobarbital (30–60 mg/kg). The increased anticonvulsant effectiveness found in this study is similar to previous findings with diazepam and phenobarbital against prekindled and kindled amygdaloid seizures, but stands in contrast to findings with prekindled and kindled pentylenetetrazol seizures.     

The effect of a glycine derivative (CP 1552-S) on kindled seizures in rats

The effects of the glycine derivative, CP 1552-S (2-N-pentylaminoacetamide hydrochloride) were evaluated for potential anticonvulsant activity in rats which were cortically- or amygdaloid-kindled. Large doses (300-600 mg/kg, i.p.) of CP 1552 given 30 min before stimulation resulted in significant reductions in duration of afterdischarge after both partially-developed and fully-developed cortically-kindled seizures. The largest dose tested (600 mg/kg, i.p.) markedly reduced the duration of the elicited afterdischarge and the severity of seizure. This dose was associated with prestimulation sedation and a 50% incidence of post-afterdischarge spontaneous, electrical seizure activity. Against kindled amygdaloid seizures, CP 1552-S significantly reduced the duration of afterdischarge at 300 mg/kg (i.p.) without modifying the seizure and without prestimulation behavioral or electrical effects. The largest dose tested (600 mg/kg, i.p.) resulted in a significant reduction of the elicited duration of afterdischarge but was associated with a 25% incidence of prestimulation spontaneous electrical seizure activity and a 45% incidence of post-afterdischarge electrical seizure activity. When CP 1552-S (30-300 mg/kg, i.p.) was administered daily, prior to the amygdaloid kindling stimulus, no difference was noted in the rate of acquisition of the kindled amygdaloid response. It is concluded that the glycine derivative CP 1552-S, has little anticonvulsant activity against the acquisition or development of kindled amygdaloid seizures. It appears to have significant anticonvulsant effects against both cortically- and amygdaloid-kindled afterdischarges with little effect on the behavioral severity of the seizure. Further, large doses of CP 1552-S appeared to result in paradoxical post-afterdischarge and possibly prestimulation electrical seizure activity.     

Effects of etomidate,ketamine or propofol,and their combinations with conventional antiepileptic drugs on amygdala-kindled convulsions in rats

Ketamine, etomidate and propofol modified behavioral and electrographic correlates of kindled seizures in rats. In detail, ketamine (5 mg/kg) and propofol (15 mg/kg) significantly increased afterdischarge threshold, reduced seizure severity and shortened seizure and afterdischarge durations. Etomidate (7.5 mg/kg) was effective in terms of seizure and afterdischarge durations. Moreover, the combinations of ketamine (2.5 mg/kg) with carbamazepine (15 mg/kg) or valproate (50 mg/kg; all drugs at their subeffective doses), reduced the severity and duration of kindled seizures. The antiseizure potency of the ketamine/carbamazepine combination was comparable to that of carbamazepine alone administered at 20 mg/kg, while the effect of ketamine/valproate was comparable to the efficacy of valproate alone at 100 mg/kg. However, the combinations of ketamine with phenobarbital or diphenylhydantoin did not exert any protective action. Propofol and etomidate entirely failed to interact with conventional antiepileptics. The combinations of ketamine with carbamazepine or valproate did not induce any significant motor impairment in the chimney test or memory deficit in the passive avoidance task. A pharmacokinetic interaction, at least in plasma, can be excluded, because ketamine (2.5 mg/kg) did not affect the free plasma concentrations of carbamazepine or valproate. Results of the present study may suggest that there may be no risk of negative interactions between injectable anesthetics and antiepileptics in cases of partial epilepsy.     

抗痫灵对大鼠杏仁核点燃效应的拮抗作用

用大鼠杏仁核点燃模型研究了抗痫灵的抗癫痫作用。每日1次电刺激杏仁基底外侧核可在第15d产生点燃效应的5期反应,刺激后放电显著延长。抗痫灵在未产生中枢镇静的剂量就能抑制点燃效应的5期反应,ED_(50)为84.7mg/kg,对刺激后放电影响较少。丙戊酸钠抑制5期反应作用较强,并能显著缩短刺激后放电时程。实验表明抗痫灵具有对抗慢性杏仁核点燃效应的作用。     

Serotonergic mechanism in seizures kindled from the rabbit amygdala

Summary The effect of agents enhancing or diminishing serotonergic activity on seizures kindled from the rabbit amygdala was examined. Acute administration of 5-hydroxytryptophan (5-HTP) 10 and 25 mg/kg (administered in combination with a peripheral decarboxylase inhibitor), quipazine 1,5 and 10 mg/kg or femoxetine 5 and 15 mg/kg which enhance serotonergic activity affected neither the intensity of behavioral seizures nor the duration of bioelectrical ones. 5-HTP 25mg/kg and femoxetine 15 mg/kg prolonged the duration of behavioral seizures. Chronic administration of 5-HTP 25mg/kg had no effect on the development of kindled seizures. Acute administration of p-chlorphenylalanine (PCPA) 250 mg/kg reduced the intensity and shortened the duration of behavioral seizures. Cyproheptadine which blocks the postsynaptic action of serotonin shortened the duration of behavioral seizures. Chronic administration of PCPA 80 mg/kg delayed the development of kindled seizures. It is concluded that a pharmacological stimulation of the serotonergic system exerts no or little enhancing effect, whereas pharmacological inhibition of this system attenuates and delays the development of seizures kindled from the rabbit amygdala.     

Pharmacological modification of amygdaloid-kindled seizures

The acute effect of several antiepileptic drugs on amygdaloid-kindled seizures was investigated in rats. Phenobarbital, diazepam and trimethadione produced a dose-dependent decrease in severity and amygdaloid afterdischarge duration (ADD) of full kindled seizures. In contrast, phenytoin did not suppress kindled seizures but appeared to increase seizure severity and ADD, suggesting that its action is fundamentally different from that of the other antiepileptic agents. The general anesthetic, ketamine, was weakly effective in abolishing established kindled seizures but had a marked ability to prevent kindling when given prophylactically from the outset of amygdaloid stimulation. The anti-kindling action of ketamine may be related to its ability to enhance central noradrenergic mechanisms.     

The effects of LY-201116 [4-amino-N-(2,6-dimethylphenyl) benzamide] on the amygdala-kindled rat

The effects of LY-201116, a 4-aminobenzamide, were examined in rats using the amygdala kindling model, both during acquisition of the kindled response and in fully kindled animals. Dose-response and time-response studies for efficacy and rotorod toxicity were completed following intraperitoneal injection of the drug. Afterdischarge duration, behavioral seizure response, kindled seizure threshold and EEG recordings were used to assess efficacy and toxicity of the drug. In the acquisition trial, the drug (7.5 mg/Kg) did not significantly alter the number of stimulations required to produce the first stage 5 kindled response nor did it modify afterdischarge durations. Doses of 11.25 and 15 mg/Kg suppressed afterdischarge and diminished behavioral responses significantly in fully kindled rats, but these doses were also neurotoxic as judged by rotorod performance. The non-selective anticonvulsant effect of 11.25 mg/Kg lasted at least 90 min. A dose of 15 mg/Kg raised kindled seizure threshold and diminished afterdischarge duration. Doses of 20, 30 and 40 mg/Kg produced spontaneous EEG spikes and seizures accompanied by behavioral convulsions. The drug thus exhibited non-selective anticonvulsant effects in fully kindled rats following doses of 11.25 or 15 mg/Kg, but exhibited proconvulsant activity following doses in the range of 20-40 mg/Kg.     

Nifedipine has paradoxical effects on the development of kindling but not on kindled seizures in amygdala-kindled rats

The effects of nifedipine, an antagonist of voltage-operated calcium channels, on the development of amygdala kindling and on the production of fully kindled seizures, stimulated from the amygdala, were investigated. Rats were treated daily with two doses (5 and 50 mg/kg, i.p.) of nifedipine during the development of kindling. Both doses of nifedipine retarded the development of kindled seizures and 50 mg/kg of nifedipine prolonged the latency to the occurrence of bilateral forelimb clonus. In contrast to these antiepileptogenic effects, however, both doses also increased the duration of afterdischarge. This resulted in a striking increase in the cumulative duration of afterdischarge, required to reach stage 4 and 5 seizures. Contrary to the results of a previous study, 50 mg/kg of nifedipine did not produce any significant effect on fully kindled seizures, regardless of the interval (5 min-24 hr) between injection and stimulation of kindling. These results suggested that although nifedipine inhibited the propagation processes of seizures during development of kindling, it appeared to increase the duration of epileptic activity at the kindling focus.     

Effect of cocaine and lidocaine on the expression of kindled seizures in the rat

The effect of cocaine and lidocaine on the expression of kindled seizures was studied in male Long-Evans rats. Animals were implanted with an electrode in either the olfactory bulb, prepyriform cortex, or basolateral amygdala and kindled by daily electrical stimulation. Each animal was then tested for the expression of kindled seizures following the intraperitoneal administration of saline, 20 mg/kg cocaine hydrochloride, or 20 mg/kg lidocaine hydrochloride. During testing the implantation site was stimulated every 60 sec at increasing current levels until an afterdischarge was elicited. Each animal was tested once under each drug at 96 hr intervals. The order of drug administration was counterbalanced across animals. Neither cocaine nor lidocaine had a significant effect on afterdischarge threshold. Both drugs significantly reduced the latency for clonus to occur following stimulation, a measure presumably related to the propagation of afterdischarges from the site of stimulation to other brain areas. In addition both cocaine and lidocaine significantly reduced the rated behavioral response to the stimulation due to a decrease in rearing and falling. Because they occurred with both cocaine and lidocaine, these effects appear to be of local anesthetic origin. In contrast, only cocaine significantly reduced afterdischarge duration, and only lidocaine significantly reduced clonus intensity. With the possible exception of clonus latency, these effects were present at all electrode sites studied. The results indicate that cocaine has pronounced effects on the expression of seizure activity in the olfactory forebrain, some of which are due to its local anesthetic action, and some not.     

Pentylenetetrazol augmentation of developing kindled amygdaloid seizures

The effects of daily administration of pentylenetetrazol (PTZ) on the rate of the development of kindled amygdaloid seizures (KAS) were tested in the rat. Rats were pretreated for 6 days with 25 mg/kg PTZ or normal saline 15 min. prior to each daily amygdaloid stimulation. The PTZ group exhibited fully developed KAS, including a maximal behavioral ranking (BR) and an afterdischarge duration (AD) of over 90 sec, in 3.8 ± 0.3 stimulations compared to 8.0 ± 0.6 stimulations (ave. ± SEM) for the saline controls. Within 10 min after dosing, PTZ consistently induced intermittent spiking of 5 sec or less in the EEG and behaviorally induced head nodding and sniffing. However, chemical kindling due to the 6 repetitive doses of PTZ was not observed. When the PTZ pretreatment was stopped on the 7th day, the BR and AD of the PTZ pretreatment group decreased from 187% and 161% of control values, respectively, to 118% and 100% of control. It appears that PTZ augments both the AD and BR of the developing KAS but does not accelerate the actual rate of the development of the KAS.     

香荚兰素对抗大鼠杏仁核点燃效应

用大鼠杏仁核点燃模型研究了香荚兰素的抗癫痫作用。每日一次低电流刺激杏仁基底外侧核可在第15天使大鼠产生典型的五期反应,刺激后放电显著延长。香荚兰素在不产生中枢抑制作用的剂量即可抑制点燃效应的五期反应,ED₅₀为286 mg/kg(ip),同时使刺激后放电时程比对照组下降28.6%。苯妥英钠抑制五期反应的ED₅₀为56mg/kg,也能明显缩短刺激后放电时程。本文提供了一种新型慢性实验性癲痫模型。     

Intracerebroventricular administration of histamine H3 receptor antagonists decreases seizures in rat models of epilepsia

The effects of histamine H3 antagonists on amygdaloid kindled and maximal electroshock seizures in rats were studied to determine their potential as new antiepileptic drugs. Under pentobarbital anesthesia, rats were fixed to a stereotaxic apparatus and a stainless steel guide cannula for drug administration was implanted into the lateral ventricle. In amygdaloid kindled seizures, electrodes were implanted into the right amygdala and electroencephalogram was recorded bipolarly; stimulation was applied bipolarly every day by a constant current stimulator and continued until a generalized convulsion was obtained. In the maximal electroshock (MES) seizure test, electroconvulsion was induced by stimulating animals through ear-clip electrodes, and the durations of tonic and clonic seizures were measured. Thioperamide, clobenpropit, iodophenpropit, VUF5514, VUF5515 and VUF4929 caused a dose-dependent inhibition of both seizure stage and afterdischarge (AD) duration of amygdaloid kindled seizures. The duration of tonic seizure induced by MES was also inhibited by H3 antagonists, but the duration of clonic seizures were unchanged. Among the H3 antagonists tested, clobenpropit and iodophenpropit were somewhat more potent than the other drugs on amygdaloid kindled seizures and MES seizures, respectively. These results indicate that some H3 antagonists may be useful as antiepileptic drugs, especially for secondary generalized seizures and/or tonic-clonic seizures in humans.     

Anticonvulsant and proconvulsant effects of inhibitors of GABA degradation in the amygdala-kindling model

The effects of three drugs, namely gamma-vinyl GABA (vigabatrin), gamma-acetylenic GABA, and aminooxyacetic acid, which increase brain GABA concentrations by irreversible inhibition of GABA degradation, were studied in amygdala-kindled rats. Vigabatrin 800 or 1,200 mg/kg i.p. 4 h after its administration, caused prolongation of behavioural seizures and electrographic afterdischarges recorded from the stimulated amygdala. One to three days after administration it dose dependently reduced seizure severity, seizure duration and afterdischarge duration in most animals. Determination of GABA levels in synaptosomes isolated from 12 brain regions of kindled rats 4 or 48 h after injection of 1,200 mg/kg vigabatrin indicated that the variable effects of this drug at different times after its administration could be related to differences in the time course of nerve terminal GABA increases in selective brain regions such as amygdala and corpus striatum. In contrast to vigabatrin, gamma-acetylenic GABA, 100 mg/kg i.p., reduced seizure severity in kindled rats as early as 4 h after its administration but afterdischarge duration increased significantly on subsequent days. Similar late increases in afterdischarge duration (and limbic seizure activity) after the time of maximum anticonvulsant effect had elapsed were also observed with vigabatrin, which could suggest that the anticonvulsant effect of such drugs is followed by withdrawal hyperexcitability. Aminooxyacetic acid, 20 mg/kg i.p., exerted no significant anticonvulsant effect in kindled rats but prolonged afterdischarge duration in several of the animals studied. The data suggest that GABA-T inhibitors, such as vigabatrin, differ from most antiepileptic drugs previously tested in the kindling model in that they may produce both anticonvulsant and proconvulsant effects at the same dose in the same animal as a function of time after administration.     

An examination of the anticonvulsant properties of voltage-sensitive calcium channel inhibitors in amygdala kindled seizures

Voltage-sensitive calcium (VSC) channels may contribute to epileptogenesis. A systematic examination of the anticonvulsant efficacy of different classes of VSC channel inhibitors, however, is lacking in chronic seizure models. The present study evaluated representatives from three different classes of VSC channel inhibitors for their protection against amygdala kindled seizures. Adult male rats (n=12) were kindled to stage 5 seizures (GS), and a threshold intensity required to evoke a GS was determined. The Ca⁺⁺-channel inhibitors (verapamil 0, 10, 20, 40 mg/kg; nimodipine 0, 5, 25, 50 mg/kg; nitrendipine 0, 25, 50, 100 mg/kg and flunarizine 0, 20, 40, 80 mg/kg) were administered 60–90 min prior to amygdala stimulation at the established threshold. None of the drugs altered threshold for inducing a seizure. Verapamil, a phenylalkylamine, and the dihydropyridines nimodipine and nitrendipine were without effect on kindled seizures. The diphenylalkylamine, flunarizine, was found to be the most efficacious, reducing AD duration and duration of clonic seizure activity by more than 60% in most animals. Flunarizine also decreased the severity of behavioral seizures, with 40% of the animals displaying Stage 1–2 seizures only. It is concluded that some VSC Ca⁺⁺-channel inhibitors do possess anticonvulsant potential. Thus influx of extracellular calcium through VSC channels may contribute to the expression of kindled seizures.Although the research described in this article has been supported by the United States Environmental Protection Agency (through contract 68-02-4450 to Mantech Environmental Technology Incorp.), it has not been subjected to Agency review and therefore does not necessarily reflect the views of the Agency and no official endorsement should be inferred. Mention of tradenames or commercial products does not constitute endorsement or recommendation for use.     

Anticonvulsant effect of allopurinol on hippocampal-kindled seizures.

This study assessed the anticonvulsant effect of allopurinol (5 and 50 mg/kg, IP) on seizures kindled from the feline hippocampus. Allopurinol at a higher dose significantly reduced the behavioral seizures stage, but not afterdischarge duration, without producing any behavioral toxicity. The present results lend experimental support to the contention that allopurinol possesses anticonvulsant efficacy in the treatment of human epilepsy.     

The effects of various anesthetics on amygdaloid kindled seizures

The effects of various doses of cataleptic anesthetics, gamma-butyrolactone (GBL), phencyclidine (PCP), and ketamine (KET), and the depressant anesthetics, pentobarbital (PB) and chloral hydrate (CH), on amygdaloid kindled seizures were tested in the rat. The seizure activity was monitored by behavioral observation and EEG recording. Anesthetic doses of the cataleptic anesthetics with the exception of KET had minimal effects on the afterdischarge duration (AD) and behavioral ranking (BR) of the elicited seizures. On the other hand, they were more inhibitory to the AD and BR than was the convulsant pentylenetetrazol (PTZ). The only cataleptic that induced spontaneous seizure activity at anesthetic doses was PCP, although KET induced epileptoid activity at supranesthetic doses. Ketamine, PB, and CH completely inhibited elicited seizure activity at anesthetic doses. In addition, rats were kindled by repetitive electrical stimulation during GBL-induced anesthesia or catalepsy. Although both these GBL groups averaged more stimulations to reach generalized seizures than the saline controls, GBL did not block the kindling process.     

Development of tolerance to clobazam in fully kindled rats: Effects of intermittent flumazenil administration

The effects of acute and chronic treatment with the 1,5-benzodiazepine, clobazam, were studied on fully kindled amygdaloid seizures in rats. After acute dosing, clobazam significantly reduced all parameters of kindled seizures (seizures severity, seizure duration, duration of amygdalar afterdischarges) at doses of 7.5 or 10 mg/kg i.p. ‘Active’ plasma concentrations of clobazam ranged between 300–800 ng/ml. The elimination half-life of clobazam in plasma was about 1 h. Only very low (10–75 ng/ml) levels of the major metabolite, N-desmethylclobazam, were detected in rats. Administration of N-desmethylclobazam indicated that plasma concentrations of at least 300 ng/ml were necessary for anticonvulsant effects. During chronic administration of clobazam, 10 mg/kg 3 times daily, marked tolerance developed to the anticonvulsant and adverse (ataxiogenic and sedative) effects of the benzodiazepine. The experiment was repeated using a different protocol with minimized environmental stimuli and no amygdala stimulation during chronic clobazam administration. The loss of effects on seizure severity and motor function was similar to the first chronic experiment, whereas the loss of effects on seizure and afterdischarge duration was less marked. This indicates that conditioning of ‘learned tolerance’ is partly involved in clobazam tolerance in kindled rats. Intermittent injection of the benzodiazepine receptor antagonist, flumazenil, 5 mg/kg i.p. every third day, did not alter the loss of pharmacodynamic effects during chronic treatment with clobazam, but seemed to prevent hyperexcitation and other abstinence symptoms in the withdrawal period. The data indicate that periodic injection of a benzodiazepine receptor antagonist does not represent a possible therapeutic approach for preventing the development of tolerance during long-term benzodiazepine exposure.     

Proconvulsant activity of endosulfan in amygdala kindling.

The proconvulsant properties of the chlorinated hydrocarbon insecticide, endosulfan, were investigated using electrical kindling of the amygdala. Male rats were implanted with electrodes in the amygdala and stimulated once daily with a standard kindling stimulus 60-90 min following endosulfan (0, 2.5, 5.0 mg/kg, PO). No alterations were observed in either the threshold to induce an afterdischarge (AD) or the duration of clonus upon seizure generalization. Endosulfan significantly reduced the number of stimulations required to produce Stage 5 generalized seizures. Seizures prior to stimulation were evident in a subset of animals from both dosage groups and were never observed in controls. The presence of kindled seizures was maintained in the absence of further dosing, as amygdala stimulation 2-4 weeks after the last endosulfan treatment resulted in generalized seizures in all animals. These results suggest that faster kindling rates induced by endosulfan are not readily attributable to transient toxicant-related increases in excitability of the nervous system. It was concluded that endosulfan has proconvulsant properties that may be related to an action on GABA within the central nervous system.