Convulsant Effects Research Articles

Genetic selection of mouse lines differing in sensitivity to a benzodiazepine receptor inverse agonist

Mice were selectively bred according to their sensitivity or their resistance to the convulsive effects of a 4-mg/kg dose of methyl β-carboline-3-carboxylate ( β-CCM), a benzodiazepine (BZ) receptor inverse agonist. The selection proved to be easy, with a clear separation of the two lines, convulsing with short latencies or resistant, already at the first generation of selection. Selection of a third line of animals convulsing with long latencies did not succeed. 3H-Ro 15-1788 binding analysis provided evidence for a strong decrease in B max in the resistant line.

Birth order and gender of heroin addicts: the role of siblings in the addict's “career” : V. Pomini, J. Liappas, V. Peppas, N. Papavasiliou, G. Christodoulou. Athens University Medical School Department of Psychiatry Vas. Sophias 72-1 1528 Athens, Greece

The anticonvulsants diazepam (1–10 mg/kg) and phenobarbital (30–100 mg/kg) protected against lethality without altering clonic convulsions induced by 75 mg/kg cocaine (CD100) in male Swiss Webster mice. In contrast, the non-competitive N-methyl-D-aspartate (NMDA) antagonists, MK-801 (dizocilpine) and phencyclidine, produced dose-dependent protection against cocaine convulsions. The competitive NMDA antagonists, CPP and NPC 12626, were also anti-convulsant, without producing the behavioral disturbances associated with non-competitive antagonists. Diazepam and phenobarbital protected against convulsions induced by 60 mg/kg cocaine (90% convulsions alone). Compounds that act at the strychnine-insensitive glycine receptor of the NMDA receptor comples, ACPC and 7-chlorokynurinic acid, also protected against convulsions induced by 60 mg/kg cocaine. In contrast, the non-opioid antitussive anticonvulsants (dextromethorphan, caramiphen, and carbetapentane) were not active against either dose of cocaine. The efficacy of compounds as antagonists of the convulsant effects of cocaine and NMDA appear related. These results suggest a potential role for the NMDA receptor complex in the convulsant actions of cocaine and new molecular targets for drug discovery in treating cocaine toxicity.

Sensitisation of withdrawal signs following repeated withdrawal from a benzodiazepine: differences between measures of anxiety and seizure sensitivity.

Three experiments examined the effect of either withdrawal from diazepam, or repeated treatment with the convulsant, pentylenetetrazol (PTZ), on behaviour and seizure threshold. The behaviours measured were on the elevated plus maze and in the four-plate test; seizure threshold was measured as dose of PTZ infused via the tail vein to the first clonic twitch. In experiment 1, we examined the effect of either single or repeated withdrawal from diazepam using a procedure in which the drug was administered SC in a slow release depot. Three cycles of withdrawal from diazepam were compared to a single withdrawal experience. A single withdrawal from diazepam following chronic treatment gave rise, 72 h following the last dosing, to behavioural changes, suggestive of anxiety, in both tests, but did not result in a reduced convulsant threshold. In contrast, repeated withdrawal resulted in a reduction in sensitivity in several measures of anxiety, but sensitised the mice to the convulsive effects of the PTZ. The unexpected failure to find an increased sensitivity to a convulsive agent following a single withdrawal from SC diazepam was examined in experiment 2. The seizure threshold following a single withdrawal of mice which had received diazepam chronically IP in aqueous vehicle was significantly reduced relative to vehicle-treated controls, whereas that of animals receiving the same dose SC in oil, was not. It is argued that the difference may arise from the animals treated repeatedly with IP diazepam unintentionally experiencing repeated withdrawal, since the half-life of the drug by this route is short. In experiment 3, repeated sub-convulsant PTZ treatment reduced the convulsant threshold (the dose of PTZ required to give rise to the first clonic twitch), but had no significant effect on the behavioural measures of anxiety compared to a single dose of PTZ or vehicle controls. The results suggest that repeated withdrawal from chronic treatments with diazepam sensitises mice to convulsant stimuli in a manner resembling the effects of repeated administration of sub-convulsant doses of PTZ, but that neither repeated PTZ nor repeated diazepam withdrawal results in increased sensitivity to anxiogenic stimuli; rather, repeated withdrawal from diazepam may reduce the susceptibility of mice to behavioural measures of anxiety.

Effects of soman-induced convulsions on phosphoinositide metabolism.

Turnover of [3H]phosphoinositides (PI) was examined in brain slices from the hippocampus of rats undergoing soman-induced seizure activity. Hydrolysis of PI was determined by measuring the accumulation of [3H]inositol-1-phosphate (IP1). Incubation of hippocampal slices in the presence of carbachol or norepinephrine (NE) increased PI hydrolysis. Stimulated hydrolysis by NE, but not carbachol was significantly reduced in slices from soman-challenged rats undergoing convulsive activity. NE-stimulated PI hydrolysis was not reduced in slices from animals exposed to soman that did not exhibit convulsive activity. In rats surviving for 24 h, the response to NE was not different from control rats. In control slices, NE-stimulated hydrolysis of PI was potentiated by GABA. No potentiation by GABA was seen in slices from animals undergoing seizures. Uptake and incorporation of myo-[2-3H]inositol into phospholipids was reduced in slices from rats undergoing convulsions. Reduced IP1 production appeared to be owing, in part, to decreased synthesis of inositol lipids. These observations suggest that during soman-induced seizure activity, there is an apparent decrease in the response of the PI second messenger system to NE stimulation, and that this may contribute to the severity and duration of convulsions and brain damage resulting from exposure to soman and other anticholinesterase compounds.

Modulation of convulsive threshold of pentylene tetrazole by zinc

In the present study which was aimed to see the effect of zinc on pentylenetetrazole induced convulsive threshold in rats we found that zinc sulfate 100 μg intracerebroventricularly) and pentylenetetrazole (50 mg/kg intraperitoneally) produced dose related seizure activity; however, pretreatment with zinc decreased the threshold, increased the severity, incidence of multiple seizures and total duration of pentylenetetrazole induced seizures. Diazepam (5 mg/kg intraperitoneally) pretreatment increased the threshold and lowered the incidence of convulsions in zinc induced seizures which further confirms that the convulsive effect of zinc is through inhibition of gamma aimino butyric acid.

The CRF 1 receptor mediates the excitatory actions of corticotropin releasing factor (CRF) in the developing rat brain: in vivo evidence using a novel, selective, non-peptide CRF receptor antagonist

Corticotropin releasing factor (CRF) is the key coordinator of the neuroendocrine and behavioral responses to stress. In the central nervous system, CRF excites select neuronal populations, and infusion of CRF into the cerebral ventricles of infant rats produces severe age-dependent limbic seizures. These seizures, like other CRF effects, result from activation of specific receptors. Both of the characterized members of the CRF receptor family (CRF 1 and CRF 2), are found in the amygdala, site of origin of CRF-induced seizures, and may therefore mediate these seizures. To determine which receptor is responsible for the excitatory effects of CRF on limbic neurons, a selective, non-peptide CRF 1 antagonist was tested for its ability to abolish the seizures, in comparison to non-selective inhibitory analogues of CRF. Pretreatment with the selective CRF 1 blocker (NBI 27914) increased the latency and decreased the duration of CRF-induced seizures in a dose-dependent manner. The higher doses of NBI 27914 blocked the behavioral seizures and prevented epileptic discharges in concurrent electroencephalograms recorded from the amygdala. The selective CRF 1 blocker was poorly effective when given systemically, consistent with limited blood-brain barrier penetration. Urocortin, a novel peptide activating both types of CRF receptors in vitro, but with preferential affinity for CRF 2 receptors in vivo, produced seizures with a lower potency than CRF. These limbic seizures, indistinguishable from those induced by CRF, were abolished by pretreatment with NBI 27914, consistent with their dependence on CRF 1 activation. In summary, CRF induces limbic seizures in the immature rat, which are abolished by selective blocking of the CRF 1 receptor. CRF 1-messenger RNA levels are maximal in sites of seizure origin and propagation during the age when CRF is most potent as a convulsant. Taken together, these facts strongly support the role of the developmentally regulated CRF 1 receptor in mediating the convulsant effects of CRF in the developing brain.

P2 purinoceptor blocker suramin antagonises NMDA receptors and protects against excitatory behaviour caused by NMDA receptor agonist (RS)-(tetrazol-5-yl)-glycine in rats.

It has been reported that suramin, an anthelminthic, trypanocidal agent and an inhibitor of P2 receptors, may antagonise N-methyl-D-aspartate (NMDA) subtype of the excitatory amino acid receptors. Both NMDA receptors and P2X subclass of P2 receptors are ligand-gated Ca2+-selective channels and, since the increased influx of Ca2+ into neurons has been linked to neurotoxicity, simultaneous inhibition of P2X and NMDA receptors in vivo by suramin could represent an effective neuroprotective treatment. We have found that suramin inhibited the binding of [3H]CGP 39653 to NMDA receptor binding sites in vitro and reduced the frequency of NMDA channel openings in patch-clamp studies. Suramin (1 mM) had no effect on [3H]kainate binding in vitro. In vivo, intracerebroventricular (I.C.V.) injections of suramin (70 nmol/brain) antagonised convulsive effects of the NMDA agonist (RS)-(tetrazol-5-yl)-glycine (TZG, LY 285265). Suramin, however, did not prevent neurotoxic lesions in the hippocampus caused by I.C.V. administration of TZG. Increasing the dose of suramin resulted in death from severe respiratory depression.

Effects of chronic lithium treatment on ornithine decarboxylase induction and excitotoxic neuropathology in the rat

Young adult rats were chronically treated with lithium (2.5 mmol/kg/day) for 16 days. The day after the last lithium administration, rats were injected s.c. with the excitotoxic convulsant kainic acid (10 mg/kg). As compared to saline controls, lithium-treated rats had no apparent attenuation of convulsions. Furthermore, the induction of brain ornithine decarboxylase and the consequent increase of putrescine levels, an index related to the convulsant effects of kainic acid, were similar in saline- and lithium-treated rats. Other rats were unilaterally injected with ibotenic acid into the nucleus basalis magnocellularis: no differences were measured in cortical choline acetyltransferase (ChAT) decrease among saline- and lithium-treated rats. In both the above experiments, apoptotic cell death was monitored in relevant brain regions of saline- or lithium-treated rats through a specific in situ labeling method for fragmented DNA. Whilst morphological evidence for a reduced damage in the olfactory cortex and hippocampus of kainic acid-injected rats was not obtained, lithium-treated rats showed a lower decrease of specific neurochemical markers: [ 3H] d-aspartate uptake and glutamate decarboxylase. This result suggests that mechanisms of recovery, absent in saline-treated animals, are elicited by the excitotoxic insult in lithium-treated rats.

Convulsant action of D,L-homocysteic acid and its stereoisomers in immature rats.

We wished to characterize the convulsant effect of homocysteic acid (HCA) in developing rats. Seizures were induced in 7-, 12-, 18-, and 25-day-old rats by intraperitoneal (i.p.) administration of D,L-HCA and in 12-day-old rats by i.p. injection of L- and D-stereoisomers of HCA. The animals were observed for 30 min after injection. The incidence, latencies, pattern of motor seizures, and all behavioral phenomena were noted. Fifty percent convulsant dose (CD50) values were calculated by probit analysis. Electrocorticograms (ECoG) were recorded after injection. HCA did not elicit minimal clonic seizures whereas generalized tonic-clonic seizures (GTCS) occurred in all the age groups studied. Flexion (emprosthotonic) convulsions occurred to postnatal day 18. ECoG recordings exhibited delta activity in younger pups and sharp graphoelements in older pups, but electroclinical correlation was poor. Young animals were more sensitive to the convulsant effect of D,L-HCA. In addition, D-HCA was significantly more effective than L-HCA in inducing both flexion and generalized seizures. Our data clearly indicate that seizures induced by HCA differ from those evoked by homocysteine. There are no qualitative differences in the motor pattern of seizures induced by the two stereoisomers of HCA, but marked differences were apparent in the very first signs of their action. These differences might be due to interaction with different glutamate receptor subtypes.

Unforgettable tetanus

Unforgettable tetanus

Convulsant activity of nonanesthetic gas combinations.

Most nonanesthetics (inhaled compounds that neither cause anesthesia when given alone nor decrease the partial pressure of a known inhaled anesthetic required to produce anesthesia) and transitional compounds (inhaled compounds that are less potent than would be predicted by the Meyer-Overton hypothesis) cause convulsions. A possible exception is the perfluoroalkane series of nonanesthetics. The present study tested whether perfluoroalkanes do provide an exception. Further, we tested whether the convulsant effects of nonanesthetic and transitional compounds were additive. The nonanesthetic perfluoropropane caused convulsions at 7.5 +/- 0.7 atm (mean +/- SD). Convulsions also were produced by perfluorocyclobutane (0.976 +/- 0.002 atm), 1,2-dichlorotetrafluoroethane (0.358 +/- 0.011 atm), 2,3-dichlorooctafluorobutane (0.085 +/- 0.007 atm), 1,2-dichlorohexafluorocyclobutane (0.055 +/- 0.007 atm), and flurothyl (0.00156 +/- 0.00039 atm). Of these, 1,2-dichlorotetrafluoroethane is a transitional compound, the remainder being nonanesthetics. The combination of flurothyl plus 1,2-dichlorohexafluorocyclobutane gave evidence of antagonism (a 17% +/- 21% deviation from additivity; P < 0.05), whereas the combination of 1,2-dichlorotetrafluoroethane plus 2,3-dichlorooctafluorobutane gave evidence of synergy (a -13% +/- 8% deviation from additivity; P < 0.05). The combinations of perfluoropropane plus perfluorocyclobutane (-4% +/- 15%), and perfluoropropane plus 1,2-dichlorohexafluorocyclobutane (-1% +/- 26%) did not produce results that deviated significantly from additivity. We conclude that pairs of these compounds either produce convulsions in an additive manner, a finding consistent with (but not proving) a common mode of action; or deviate modestly from additivity, a finding suggesting that at least a portion of the mechanistic basis for convulsions might differ, particularly for flurothyl plus other nonanesthetics, or for the combination of non-anesthetics and transitional compounds.

Convulsive effects of a benzodiazepine receptor inverse agonist: Are they related to anxiogenic processes?

The linkage-testing strain of ABP Le mice carries six mutations which express in easily identifiable phenotypes. By crossing this strain with a traditional inbred strain ( C57BL 6ByJ ) which is the ‘wild type’ for the mutated ABP Le loci, we produced Mendelian populations, intercrosses and backcrosses so as to estimate whether the sensitivity to methyl β-carboline-3-carboxylate (β-CCM), a benzodiazepine receptor inverse agonist, and anxiety-related behaviour could be related to a common genetically determined substrate. We have shown that one locus on chromosome 9 is associated with β-CCM-induced seizures and three loci on chromosomes 4, 7 and 9 are associated with anxiogenic processes. Analysis of [ 3H]flumazenil binding suggested a possible involvement of a B max decrease in both β-CCM-induced seizures and anxiogenic processes. The putative common genetic regulation of both mechanisms is discussed.

Effects of some excitatory amino acid antagonists and drugs enhancing gamma-aminobutyric acid neurotransmission on pefloxacin-induced seizures in DBA/2 mice.

The behavioral and convulsant effects of pefloxacin (PEFLO), a quinolone derivative, were studied after intraperitoneal (i.p.) administration to Dilute Brown Agouti DBA/2J (DBA/2) mice, a strain genetically susceptible to sound-induced seizures. The anticonvulsant effects of some excitatory amino acid (EAA) antagonists acting at N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) receptors and of some compounds enhancing gamma-aminobutyric acid (GABA)-ergic transmission against seizures induced by PEFLO were also evaluated. The present study demonstrated that both groups of compounds administered i.p. or intracerebroventricularly were able to protect against seizures induced by PEFLO. However, ifenprodil and (+/-)-alpha-(chlorophenyl)-4-[(4-fluorophenyl)methyl]-1-piperidine-ethan ol (SL 82.0715), two compounds acting on the polyamine site of the NMDA receptor complex, were unable to provide any protection. The relationship between the different sites of action and the anticonvulsant activities of these derivatives were discussed. Although the main mechanisms of PEFLO-induced seizures cannot be easily determined, potential interactions with the receptors of EAA exist. In fact, antagonists of EAA, and in particular, those acting at NMDA receptors, were able to increase the threshold for the seizures or to prevent the seizures induced by PEFLO, while compounds acting at the polyamine site did not provide any protection. The AMPA-KA receptor antagonists were also able to exert anticonvulsant activity, but with minor potency in comparison to those of NMDA antagonists. In addition, the fact that compounds enhancing GABA-ergic neurotransmission were also able to protect the mice against seizures induced by PEFLO suggests an involvement of GABA system.

The role of nitric oxide in focally-evoked limbic seizures

The deep rostral piriform cortex contains a site (area tempestas) in which focal application of picomole amounts of bicuculline, a GABA antagonist, triggers limbic motor seizures which are dependent upon activation of both N-methyl-d-aspartate and α-amino-3-hydroxy-5-methyloxole-4-proprionate subtypes of glutamate receptors. In the present study we determined whether nitric oxide can influence the local modulation of seizure initiation by bicuculline. Nitric oxide and the nitric oxide precursor l-arginine, alone or in combination with low doses of bicuculline were focally administered into the area tempestas of rats. While nitric oxide alone had no significant convulsant effect, l-arginine alone (30–240nmol) induced brief myoclonic episodes. Nitric oxide (0.7nmol) and l-arginine (30nmol) markedly potentiated the seizures evoked by a low dose of bicuculline. The effect of l-arginine was prevented by focal pretreatment with an inhibitor of nitric oxide synthesis, N-nitro-l-arginine methyl ester. However, N-nitro-l-arginine methyl ester did not attenuate the convulsant effect of bicuculline or kainate alone when focally administered into area tempestas.The data demonstrate that exogenously applied nitric oxide or its precursors can enhance seizure triggering activity. However, the data also indicate that l-arginine-nitric oxide pathway does not normally contribute to seizure expression from area tempestas, as N-nitro-l-arginine methyl ester alone did not attenuate focally-evoked seizures.

Amygdala-kindled seizures increase the expression of corticotropin-releasing factor (CRF) and CRF-binding protein in GABAergic interneurons of the dentate hilus

Kindling, a model of temporal lobe epilepsy, induces a number of neuropeptides including corticotropin-releasing factor (CRF). CRF itself can produce limbic seizures which resemble kindling in some aspects. However, tolerance to the convulsant effects of CRF develops rapidly. Hypothetically, this could be explained should seizures also induce the CRF-binding protein (CRF-BP), which has been postulated to restrict the actions of CRF. Therefore, in the present study, we used in situ hybridization to examine the effects of amygdala-kindled seizures on the mRNA levels of CRF and CRF-BP. Kindled seizures markedly elevated CRF and CRF-BP in the dentate gyrus of rats. CRF and CRF-BP were induced almost exclusively in GABAergic interneurons of the dentate hilus. The CRF and CRF-BP interneurons also expressed neuropeptide Y but not cholecystokinin. CRF appeared to have an excitatory role in the dentate gyrus as it decreased the afterhyperpolarization of dentate granule neurons. These results suggest that CRF may contribute to the development of amygdala kindling. However, the compensatory induction of CRF-BP may serve to limit the excitatory effects of CRF in the dentate gyrus.

Neurophysiological Effects ofEuphorbia hirta L. (Euphorbiaceae)

A lyophilized aqueous extract of Euphorbia hirta L. (Eh) has been evaluated for benzodiazepine-like properties and for hypnotic, neuroleptic and antidepressant properties, in order to complete the study of dose-dependent sedative and analgesic effects previously demonstrated. The plant extract did not protect mice against the convulsant effects of pentylenetetrazol, it did not cause muscle relaxant effects and it did not seem to possess any affinity for benzodiazepine receptors. In addition, Eh did not have its own hypnotic effects in mice, but it intensified those of barbiturates, and caused a direct action on the central nervous system. This aqueous extract did not possess neuroleptic activity, but slight antidepressant effects were obtained against reserpine-induced ptosis and oxotremorine-induced hypothermia.

Antidepressants and seizures: Clinical anecdotes overshadow neuroscience

Pharmacological treatment of depression in persons with epilepsy has been an area of controversy because some drugs commonly are perceived specifically to induce or exacerbate seizures in patients with seizure disorders. This prevailing misconception is unjustified by scientific studies, yet it continues to prevent afflicted persons from receiving appropriate therapy. The scientific literature shows that tricyclic antidepressant drugs cause seizures in overdose in both animals and humans. In lower doses, these drugs have anticonvulsant activity in humans and animals. Thus, the antidepressant drugs are like several antiepileptic drugs that can both prevent and cause seizures. The anticonvulsant activity of antidepressant drugs has been studied extensively in animals and almost certainly stems from their capacity to block norepinephrine and/or serotonin reuptake. The pharmacodynamic action responsible for their convulsant effects has not been well studied but may be due to their local anesthetic, antihistaminic, or antimuscarinic activity. The newer, more selective monoamine uptake blockers have very low convulsant liability, and it is suggested that their anticonvulsant activity, which is well documented in animals, be investigated further in humans. If their effects in humans are analogous to those in animals, these drugs can be used safely in epileptic patients with depression, and it is possible that their anticonvulsant activity can be exploited for use in the treatment of epilepsy.

The influence of repeated systemic penicillin injections at subconvulsive doses on spontaneous spike-wave discharges in the rat.

Changes in nonconvulsive spontaneous epileptic activity-Spike-Wave Discharges (SWD)-induced by repeated intraperitoneal (i.p.) administration of crystalline penicillin (PC) at subconvulsive doses were evaluated in imp-DAK rats. Three groups received ten daily i.p. injections of PC at doses of 750,000, 500,000 and 250,000 IU/kg b.w. For comparison, another classic convulsant, pentylenetrazol (PTZ) was applied in the same way to another group. PTZ was also given to all rats before and after injection series for better evaluation of changes in CNS excitability. Repeated PC injections resulted in a progressive increase in the basal level of the spontaneous SWD activity and in an increase in the SWD response to PC, which was statistically significant in the case of the dose 750,000 IU/kg. Moreover, in all rats given PC the response to PTZ (increase in SWD activity) was reduced. The results obtained in this and previous experiment suggest that in the course of repeated systemic Pc administration adaptive changes in the rat CNS develop which prevent the convulsive effects of Pc but promote the occurrence of the spontaneous nonconvulsive SWD activity.

Effects of convulsant and anticonvulsant agents on memory in squirrel monkeys

1. 1. It has been reported that subconvulsive doses of convulsant agents such as strychnine and pentylenetetrazole can enhance memory in rodents studied under various behavioral procedures. The present study was designed to determine if similar results might be obtained in squirrel monkeys. 2. 2. Responding by squirrel monkeys was maintained by food presentation under a repeated acquisition of behavioral chains procedure. Each subject acquired a different three-response chain each session. 3. 3. Sequence completions were reinforced under a fixed-ratio 5 schedule (FR 5) and errors produced a brief timeout. After the subject reached a predetermined acquisition criterion, the session was stopped and a 24 hr delay was interposed. Following the delay, the subject was retested on the same discrimination and retention was quantified as percent savings. 4. 4. When administered immediately after the subject reached the acquisition criterion, strychnine (0.0056 –0.18 mg/kg) and pentylenetetrazole (0.32–42 mg/kg) neither enhanced nor disrupted percent savings under the 24 hour delay. Similarly, the delta opioid agonist, BW373U86 (0.0056–3.2 mg/kg) [(±)-4-((α-R ∗)-α-((2S ∗, 5R ∗)-4-allyl-2,5-dimethyl-l-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide dihydrochloride], had little or no effect on percent savings following a 24 hr delay. This was true even at doses of BW373U86 which produced convulsions. In contrast, triazolam (1–1.8 mg/kg) decreased percent savings following the 24 hr delay at doses which had little or no effect on response rate. 5. 5. These results suggest that at subconvulsive doses, convulsant agents have little or no effect on memory storage, while at higher doses agents such as triazolam can disrupt memory processes in squirrel monkeys.

Anticonvulsant effect of felbamate in the pentylenetetrazole kindling model of epilepsy in the rat.

The present study was designed to examine the ability of felbamate, a novel antiepileptic agent, to antagonize the increase in seizure severity (i.e., chemical kindling) produced by chronic treatment with initially subconvulsant doses of pentylenetetrazol (PTZ). Rats were treated with PTZ (30 mg/kg, i.p., three times a week) for 8 consecutive weeks. Two other groups of rats received felbamate (300 or 400 mg/kg, i.p.), 90 min before each dose of PTZ. Pretreatment with felbamate at either dose prevented the progression of rank of seizures during chronic treatment with PTZ. Thus, the mean seizure score by the end of the chronic treatment (0-5 scale) was 0 in vehicle treated controls, 3.3 in rats treated with PTZ alone, 1.5 in rats treated with PTZ plus felbamate (300 mg/kg, i.p.) and 0.9 in the group treated with PTZ plus felbamate (400 mg/kg, i.p.). Felbamate also antagonized the long-term increase in the sensitivity to the convulsant effects of GABA function inhibitors observed in PTZ-kindled rats. Thus, the administration of a challenge dose of isoniazid (120 mg/kg, s.c.), picrotoxin (1.5 mg/kg, i.p.) or PTZ itself (15 mg/kg, i.p.), 15 to 45 days after the end of the chronic treatment regimen, induced convulsions in > 80% of PTZ-kindled rats and in < 20% of rats treated with PTZ + felbamate (400 mg/kg). The results are discussed in terms of the multiple mechanisms that can contribute to the anticonvulsant action of felbamate in the PTZ kindling model of epilepsy.