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.     

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.     

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.     

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.     

Role of AMPA and GluR5 kainate receptors in the development and expression of amygdala kindling in the mouse

The role of AMPA and GluR5-containing kainate receptors in the development and expression of amygdala kindling was examined using the selective 2,3-benzodiazepine AMPA receptor antagonist GYKI 52466 [(1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2, 3-benzodiazepine] and the decahydroisoquinoline mixed AMPA receptor and GluR5 kainate receptor antagonist LY293558 {(3S,4aR,6R, 8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline- 3-carboxy lic acid)}. Administration of GYKI 52466 (5-40 mg/kg, intraperitoneally) and LY293558 (10-40 mg/kg, intraperitoneally) prior to daily kindling stimulation in mice produced a dose-dependent suppression of the rate of development of behavioral kindled seizure activity and reduced the duration of the stimulation-induced electrographic afterdischarge. In drug-free stimulation sessions after the initial drug-treatment sessions, there was an acceleration in the rate of kindling development compared with the rate during the preceding drug-administration period; the "rebound" rate was also greater than the kindling rate in saline-treated control animals. In fully kindled animals, both GYKI 52466 and LY293558 produced a dose-dependent suppression of evoked seizures (ED(50), 19.3 and 16.7 mg/kg, respectively). Although AMPA receptors appear to be critical to the expression of kindled seizures, since kindling development progressed despite the suppression of behavioral seizure activity, AMPA receptors are less important to the kindling process. LY293558 was modestly less effective at suppressing behavioral seizures during kindling and was not superior to GYKI 52466 in retarding the overall extent of kindling development, indicating that GluR5 kainate receptors do not contribute to epileptogenesis in this model.     

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 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 lamotrigine upon development of cortical kindled seizures in the rat.

The effect of lamotrigine, a novel potential antiepileptic drug, upon the development of kindled cortical seizures was investigated in rats. Although lamotrigine, at all doses tested, failed to block or reduce the rate of development of kindling, it did have a profound effect upon the production of both non-kindled and kindled responses. All doses (3, 6, 12 and 18 mg/kg) produced a significant increase in the number of nil responses (where stimulation failed to evoke a behavioural clonus or afterdischarge) and a decrease in non-kindled responses. Doses of 12 and 18 mg/kg also significantly reduced the number of kindled responses and the duration of the kindled seizure. It is suggested that these effects of lamotrigine result from its ability to inhibit the release of glutamate, an excitatory amino acid which has been implicated in the production of kindled seizures. In contrast to previous studies on the development of kindling, it was found that in the groups which received either 12 or 18 mg/kg lamotrigine, it was possible to produce kindling without evoking any nonkindled afterdischarge. This finding is discussed in the light of the current theories surrounding the kindling process. This study suggests that lamotrigine, as well as possibly being of value in the treatment of complex partial and generalised (tonic-clonic) seizures, may also be of value in the treatment of elementary (simple) partial seizures.     

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.     

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.     

Repeated administration of subconvulsant doses of GABA antagonist drugs

Repeated subconvulsant doses of the GABA antagonist drugs picrotoxin (5 mg/kg), pentylenetetrazol (PTZ) (30 mg/kg), and bicuculline (3.5 mg/kg), were given IP once daily to rats. Picrotoxin produced rapid kindling to full seizures in about 5 days, PTZ produced sporadic myoclonic seizures after 17 days, PTZ produced sporadic myoclonic seizures after 17 days whereas bicuculline only produced occasional mild jerking. Following these treatments, seizure thresholds to these drugs were measured by an IV infusion method to minimise problems of systemic uptake and metabolism of the drugs. Picrotoxin- and PTZ-treated animals showed no alteration in seizure threshold. However, following bicuculline pretreatment, seizure threshold was raised. Methodological problems in the interpretation of pharmacological kindling are discussed.     

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.     

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.     

Effect of pentylenetetrazol-induced convulsions on the development and expression of limbic kindled seizures

Male Long-Evans rats experienced three convulsions induced by intravenously administered pentylenetetrazol (PTZ) and were then kindled by electrical stimulation of the olfactory bulb or amygdala. Pretreatment with PTZ did not alter the rate of kindling in either site but did enhance the expression of kindled seizures once generalization had occurred (PTZ-treated animals had significantly longer motor seizures, measured by clonus duration, than did saline-treated controls). This suggests that PTZ-induced convulsions have selective effects on areas of the brain that are involved in the expression of the motor seizure. In addition, rats treated with PTZ after kindling had convulsions that were significantly longer in duration than any of their three pre-kindling convulsions, indicating that kindling produced an increased sensitivity to PTZ's convulsant effects. Comparison of this experiment with previous research suggests that the ability of a drug treatment to generate a kindling-like effect is related to the pattern of seizure activity that it produces.     

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.     

Dose-dependent proconvulsant and anticonvulsant actions of the alpha 2 adrenergic agonist, xylazine, on kindled seizures in the rat

The effects of the alpha 2 adrenergic agonist, xylazine, was evaluated on kindling acquisition and on kindled seizure expression in rats. Dose-dependent proconvulsant and anticonvulsant properties were found. The proconvulsant effects were observed at low (0.3 mg/kg) doses. In previously kindled rats these consisted of a decrease in afterdischarge threshold and an increase in the length and severity of the accompanying seizure. This dose also facilitated the rate of kindling in naive subjects. The anticonvulsant effects were observed at higher dose levels (3-20 mg/kg) which also produced sedation and ataxia. If these effects upon kindling are related to the adrenergic actions of xylazine, then it is proposed that the proconvulsant effects are associated with alpha 2 receptor activation and the anticonvulsant effects with alpha 1 receptor activation.     

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.     

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.     

Antiepileptogenic effects of the novel synthetic neuroactive steroid,ganaxolone, against pentylenetetrazol-induced kindled seizures: Comparison with diazepam and valproate

Pharmacological treatment of epilepsy is often unsatisfactory due to side effects and the lack of drugs that control the progressive epileptogenic process. Modulation of inhibitory γ-aminobutyric acid (GABA)-ergic neurotransmission by synthetic agonists of the neuroactive steroid binding site on the GABA_A receptor complex is one approach toward the identification of improved antiepileptic agents. In this study, antiepileptogenic and anticonvulsive effects of the novel synthetic neuroactive steroid, ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), were evaluated in comparison with diazepam and valproate against pentylenetetrazol (PTZ)-induced kindled seizures in mice. Kindled seizures provide a model of the progressive epileptogenic process. Successive administration of 45 mg/kg PTZ on days 1, 3, 5, 8, and 10 resulted in the rapid development of kindled seizures and significant reductions in thresholds for clonic convulsions, tonic convulsions, and lethality induced by PTZ on day 10. Ganaxolone, diazepam, and valproate dose-dependently protected against clonic convulsions induced by acute submaximal dose of PTZ (70 mg/kg). The compounds also dose-dependently suppressed fully kindled seizures and blocked the expression of kindled seizures over successive treatments with PTZ (45 mg/kg). Relative to acute anticonvulsive potencies against 70 mg/kg PTZ, however, ganaxolone was more potent than valproate or diazepam against fully kindled seizures and in blocking the expression of kindled seizures over successive treatments with PTZ. Importantly, only ganaxolone demonstrated antiepileptogenic activity by blocking the development of kindling, as evidenced when PTZ was administered in the absence of anticonvulsant treatments. Both diazepam and valproate failed to prevent development of kindled seizures even at doses that fully suppressed motor expression of seizures during kindling acquisition. Unlike diazepam and valproate, ganaxolone did not impair ambulatory activity within the dose range used in this study. These data, taken in conjunction with other findings on the unique pharmacological actions of ganaxolone, predict an improvement in the pharmacological management of epilepsy with this synthetic neuroactive steroid. Drug Dev. Res. 44:21–33, 1998. © 1998 Wiley-Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America.