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

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

Effect of cocaine and pentylenetetrazol on cortical kindling

The effect of drug-induced convulsions on subsequent cortical kindling was studied in male Long-Evans rats. Animals experienced three intravenous infusions of physiological saline at 3 day intervals, or three convulsions induced by the infusion of cocaine or pentylenetetrazol (PTZ). Beginning eight days after the last infusion, all animals were kindled by stimulation of the anterior neocortex (area 6). PTZ-induced convulsions facilitated the development of both the behavioral convulsion and the electrographic seizure during cortical kindling, while cocaine-induced convulsions facilitated only the development of the electrographic seizure. Comparison of these results with previous research indicates that convulsions induced by these two drugs have long-lasting effects on brain function which differ both in their anatomical distribution and in the nature of the effects produced. These drugs also differed in their acute effects at subconvulsant doses on the expression of cortically kindled seizures. Cocaine (and lidocaine, another local anesthetic) substantially elevated afterdischarge (AD) threshold and inhibited the focal component of the cortically kindled seizure. PTZ had no significant effect on either of these variables but significantly increased AD duration. In addition to these drug effects, a substantial inhibitory effect on seizure expression was observed, both during kindling and afterwards, when ADs were elicited daily but not when they were separated by 3 days or more. This finding suggests that the large number of ADs typically required for cortical kindling may be due in part to daily stimulation.     

Phencyclidine raises kindled seizure thresholds

Phencyclidine (PCP) has been reported to have both anesthetic and seizure-inducing properties. In the present experiment the effect of PCP on previously established seizures, kindled in the amygdala, was examined, using rats as subjects. In a repeated measures design three doses of PCP (1, 2 and 5 mg/kg) were compared with a saline control condition. The high dose of PCP was found to significantly increase seizural afterdischarge thresholds, while not affecting seizure durations.     

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.     

Caffeine modification of kindled amygdaloid seizures

Rats were kindled during exposure to caffeine (50 mg/kg) or saline given IP twenty minutes before daily electrical stimulation of the amygdala until 3 kindled amygdaloid seizures (KAS) occured. They were then stimulated for 3 days without drug pretreatment followed by 5 additional days with drug pretreatment. There were no significant differences between the two groups in the number of daily stimulations or in the total seconds of cumulative afterdischarge (AD) needed to reach the first KAS. During kindling, the daily average AD tended to be longer in the caffeine treated group. This difference became significant (>200% saline) when the KAS was reached. When KAS animals were stimulated without caffeine pretreatment, the average AD returned to control lengths. When put back on caffeine pretreatment, the average AD was again increased. Caffeine (6–50 mg/kg, IP) was also evaluated in previously kindled rats using suprathreshold (400 μAMP) and threshold (20 μA increments) seizures. Caffeine had no consistent effect on threshold values. However, 12–50 mg/kg of caffeine increased seizure severity and AD durations after threshold stimulation. With suprathreshold stimulation, the length of the AD was significantly increased only after the highest dose of caffeine. It would appear that caffeine lengthens induced afterdischarges both during the acquisition phase of kindling and in the fully kindled subject. Caffeine does not appear to lower seizure thresholds or increase the rate of aquisition of the KAS in the doses tested in this model. It is postulated that caffeine may modify the KAS through an inhibition of the mechanisms which terminate the elicited AD.     

Ketamine-induced changes in kindled amygdaloid seizures

The effects of ketamine on seizures kindled by repetitive electrical stimulation of the amygdala were determined in the rat. The response of fully developed kindled amygdaloid seizures (KAS) to 20, 40, 80 and 120 mg/kg (i.p.) ketamine, administered from 5 to 60 min prior to elicitation of seizures was examined. Ketamine reduced the afterdischarge duration (AD) and behavioral response (BR) in a dose-dependent fashion. However, the effect of ketamine on the afterdischarge duration and behavioral response was not clearly time-dependent for each dose (20–120 mg/kg). A dose-dependent increase in the seizure spiking frequencies in the amygdala and cortex during kindled amygdaloid seizures was also induced by ketamine. Blood plasma and brain levels of ketamine and its metabolites were determined 15 min after 20, 40, 80 and 120 mg/kg ketamine as well as 60 min after 80 mg/kg ketamine. Brain and plasma levels of ketamine and nor-ketamine were similar to those previously reported. Low plasma levels of dehydro-nor-ketamine were seen only at 60 min after 80 mg/kg ketamine. The decrease in afterdischarge duration and behavioral response and the increase in afterdischarge duration spiking frequency seen at 15 min correlated with elevated levels of ketamine and nor-ketamine in brain and plasma. However, by 60 min plasma levels of ketamine remained high, yet the brain levels of both ketamine and nor-ketamine had decreased. This is despite the fact that afterdishcarge duration and behavioral response were still attenuated and afterdischarge duration spiking frequency was still increased. Thus, the exact contribution by ketamine and nor-ketamine to the alteration of afterdischarge duration, behavioral response and afterdischarge spiking frequency cannot be made at this time. It was apparent that inhibition of the afterdischarge duration and behavioral response along with an increase in spiking frequency was not dependent on dehydro-nor-ketamine. The possibility that an unidentified metabolite may contribute to the modification of kindled amygdaloid seizures by ketamine is discussed.     

A pharmacological study in the kindling model of epilepsy

The anticonvulsant properties of carbamazepine were evaluated in the kindled amygdaloid seizure model in rats. Carbamazepine significantly raised the threshold for seizures, reduced the duration of elicited afterdischarges and attenuated the severity of seizures in previously-kindled rats, at doses that did not cause sedation or ataxia. A similar reduction in the duration of elicited afterdischarges and severity of seizures was seen after suprathreshold stimulation (400 mu A) with doses of carbamazepine that were without obvious sedative or ataxic effects. After acute intraperitoneal injections (solvent = 2% Tween-80 and 70% propylene glycol), the maximum anticonvulsant effectiveness against suprathreshold stimulation was seen at 30 min. When administered daily (13 days) during acquisition or development of kindling, carbamazepine (25 and 50 mg/kg, i.p.) had variable effects on kindling. Neither dose consistently reduced the duration of elicited afterdischarges during the acquisition phase. Both groups tended to reduce the developing seizure, with the smaller dose of carbamazepine (25 mg/kg) resulting in a more consistent and significant reduction in severity of seizures. No significant differences in number of daily stimulations needed to reach fully kindled seizures were found. Previous studies have reported variable results with carbamazepine and the kindled amygdaloid seizure in rats. The present study provides a comprehensive evaluation of carbamazepine in this model of epilepsy and discusses the results with regard to the finding reported previously.     

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.     

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.     

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.     

Opiate modification of amygdaloid-kindled seizures in rats

Male Long-Evans rats were stereotaxically implanted bilaterally with bipolar electrodes in the central amygdala. Rats were then kindled once daily for 1 sec until 3 consecutive Stage V [25] kindled seizures were elicited. On the following day, animals were injected (IP) with either saline, naloxone (10 mg/kg), naltrexone (10 mg/kg) or morphine sulfate (10 mg/kg) and again stimulated parameters the kindling stimulation parameters. Saline injected animals continued to show long bilateral AD's and behaviors (i.e., forelimb clonus, rearing, falling) typical of Stage V kindled animals. In contrast, rats injected with naloxone or naltrexone showed reduced behavioral seizures. Potentiation of post-ictal spiking by morphine in amygdaloid-kindled rats was also observed supporting previous reports [7,21]. In a second experiment, the reduction of kindled seizure severity by naloxone was systematically replicated. It is concluded that opiates can significantly modify amygaloid-kindled seizures, and that brain endorphins may play a role in the development of maintenance of an amygdaloid-kindled seizure focus.     

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 effect of exogenous GM1 ganglioside on kindled-amygdaloid seizures

The effects of 12 daily doses of 30 mg/kg GM1 ganglioside i.p. on the acquisition of kindled-amygdaloid seizures in the rat was studied. No modification in the rate of kindling or the expression of the elicited seizures was noted during the acquisition phase. Further studies with additional fully amygdaloid kindled rats failed to show significant modification of suprathreshold or threshold elicited seizures after single 30-60 mg/kg i.p. doses of GM1 ganglioside. Despite previous studies which have shown antibodies to GM1 ganglioside to be convulsive, no anticonvulsant activity was demonstrated in this study with exogenous GM1 ganglioside using a battery of kindled-amygdaloid seizure tests in the rat.     

The effect of the NMDA receptor antagonist, MK-801, on the course and outcome of kindling

A rapid kindling procedure was used to distinguish between the anticonvulsant activity of drugs and their ability to retard the kindling process. MK-801 is a specific ligand at the phencyclidine (PCP) recognition site, and acts as a noncompetitive antagonist of NMDA-type glutamate/aspartate receptors. Intraperitoneal injections of MK-801 (0.5-4.0 mg/kg IP) significantly reduced the cumulated effect of 12 2-hr kindling stimulations, as determined from behavioral measures of seizure activity in immediately ensuing 24-hr drug-free kindling sessions; however, the corresponding electrographic effects did not reach significance. MK-801 also showed significant anticonvulsant activity when injected in fully kindled rats. Higher doses tested were accompanied by locomotor and postural effects. The anticonvulsant benzodiazepine, clonazepam, formulated with a proprietary diluent (as Rivotril, Roche), injected in anticonvulsant doses during the first 12 kindling sessions (0.64 mg/kg IP, repeated after 9 hr) did not significantly affect the course of subsequent sessions of drug-free kindling. Systemic injections of kynurenic acid (300-600 mg/kg IP 4 hours), a nonspecific antagonist of glutamate receptors in vitro, were without significant anticonvulsant or antikindling activity. Activity of NMDA-sensitive glutamate/aspartate receptors associated with the PCP recognition site may induce lasting facilitation of neural transmission; this facilitation may be responsible for the remote propagation and progressive enhancement of seizure activity kindled in the amygdala. The facilitatory process appears to be antagonised by MK-801.     

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.     

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.     

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.     

Effects of alcohol on kindled seizure thresholds in rats

Seizures were kindled in the amygdala and ventral hippocampus of rats until a stage 5 (clonic convulsion) was elicited. Stage 5 thresholds were then determined. Animals were then injected with either saline, or a 600 mg/kg, or 1600 mg/kg dose of 25% ethanol. The effect of each of these injections on seizure thresholds was assessed. The 1600 mg/kg dose caused a significant elevation in both AD and motor seizure thresholds, relative to the 600 mg/kg dose and saline, which did not differ. The elevation of seizure thresholds was significantly greater for animals with seizures kindled in the ventral hippocampus.     

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.