Effects of acute and repeated zolpidem treatment on pentylenetetrazole-induced seizure threshold and on locomotor activity: Comparison with diazepam

Zolpidem and diazepam are widely used drugs acting via benzodiazepine binding sites on GABA_A receptors. While diazepam is non-selective, zolpidem has a high affinity for α1-, and no affinity for α5-containing receptors. Several studies suggested that behavioral effects of zolpidem might be more similar to classical benzodiazepines than previously thought. To compare the sedative and anticonvulsant properties of these drugs and to evaluate the importance of GABA_A receptor subunits for development of tolerance during chronic treatment, we tested the effects of acute and repeated administration of zolpidem and diazepam on ambulatory locomotor activity (a measure of sedation) and on the threshold for myoclonic, clonic and tonic seizures in response to i.v. infusion of pentylenetetrazole (PTZ). Both drugs given acutely in doses 0.3, 1 and 3 mg/kg reduced locomotion, and in doses 1 and 3 mg/kg elevated the threshold for PTZ-induced seizures. The effects of zolpidem and diazepam on the tonic seizure threshold were greater than on myoclonus and clonic seizure threshold. Diazepam and zolpidem (3 mg/kg), given 18 or 42 h after repeated drug treatment (10 days, 5 mg/kg, twice daily), decreased the PTZ seizure threshold and increased the locomotor activity as compared to control mice, indicating development of tolerance to their anticonvulsant and sedative effects. After repeated treatment the PTZ seizure threshold was not different between the two drugs, while differences in sedation became larger than after the acute treatment. The results suggest that α5-containing GABA_A receptors are not crucial for the development of sedative and anticonvulsant tolerance.     

Enhanced susceptibility of pentylenetetrazole kindled mice to quinolone effects.

The present study was designed to examine the ability of different quinolones to affect the seizure severity and the latency of development of chemical kindling produced by repeated treatment using a subconvulsant dose of pentylenetetrazole (PTZ). A group of mice (kindled control) were treated subcutaneously (s.c.) with vehicle + PTZ (30 mg/kg, three times a week) for 6 consecutive weeks and the changes in excitability associated with the kindling state were observed over the following 2 h. A second group of mice were injected intraperitoneally (i.p.) with the following quinolone derivatives, ciprofloxacin (ciprox), pefloxacin (peflox), ofloxacin (oflox), cinoxacin (cinox), nalidixic acid (nalidixic), 1-cyclopropyl-6-amino-7-tetrahydroisoquinoline-8-methyl-4-oxo-1,4-dihydr oquinoline-3-carboxylic acid (M5) and 1-cyclopropyl-7-tetrahydro-isoquinoline-8-methyl-4-oxo-1,4-dihydroquinol ine-3-carboxylic acid (MH5) at a dose of 20 mg/kg 15 min before receiving a subconvulsant dose of PTZ (30 mg/kg, s.c.). The results showed that pretreatment with some of the quinolones tested facilitated the development of kindling to PTZ-induced seizures. In particular, ciprox, peflox, oflox, M5 and MH5 derivatives variously increased the development of kindling to PTZ induced seizures, whilst cinox and nalidix did not significantly affect it. Additionally we determined whether the enhanced susceptibility of kindled mice only occurred after relatively short intervals following the last seizure or whether it was a more permanent phenomenon. For the study of the persistence of kindling, the animals were rechallenged with the kindling stimulus (PTZ 25 mg/kg, s.c.) 15 and 30 days after the last injection of the chronic treatment with PTZ (30 mg/kg, s.c.) and the behavioural changes in the kindled mice were compared with the control ones (chronically treated with vehicle). The present data demonstrated that kindling produced long-lasting alterations, substantiating that epileptogenesis initiated by kindling renders the brain more susceptible to central nervous system (CNS) side effects of quinolones. An interaction between PTZ and quinolone derivatives which involves either an inhibition of gamma-aminobutyric acid (GABA) neurotransmission or/and an increase in the function of the excitatory amino acid (EAA) system is suggested.     

Amiloride protects against pentylenetetrazole-induced kindling in mice

This study was performed to investigate whether or not amiloride, a sodium-hydrogen exchanger (NHE) inhibitor, can protect against seizure development of pentylenetetrazole (PTZ)-induced kindling in mice.Kindling was induced by once every 2 days treatment with PTZ (25 mg kg(-1) i.p.) for 5 weeks. Challenge experiments were carried out after 15 or 30 days of last treatment with PTZ. Administration of amiloride (2 h before PTZ, in doses of 0.65 and 1.3 mg kg(-1), p.o.) significantly prolonged the onset of kindling and reduced the incidence and severity of seizures in a dose-dependent manner. The effect of amiloride on the incidence of PTZ-induced seizures was evident even after 15 or 30 days of last treatment. The results indicate a protective role for amiloride against PTZ-induced kindling in mice. The possibility of mediation of such effects by NHE inhibition is discussed.     

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.     

Purinergic modulation of the seizure threshold for pentylenetetrazol in the rat

The effects of various metabolically-stable analogs of adenosine on the threshold for seizures in rats was determined by measuring the dose of pentylenetetrazol (PTZ), infused through a tail vein, required to elicit a myoclonic jerk. The adenosine receptor agonists, 2-chloroadenosine (2-ClAdo), cyclohexyladenosine (CHA) and L- and D-phenylisopropyladenosine (L- and D-PIA), all produced dose-dependent elevations of the seizure threshold for pentylenetetrazol in rats. L-Phenylisopropyl-adenosine was the most potent analog of adenosine tested with a dose as small as 5 micrograms/kg (i.v.) producing a 23% increase in seizure threshold for pentylenetetrazol. The rank order of the potency of adenosine agonists in increasing the seizure threshold was L-PIA greater than 2-ClAdo greater than CHA greater than D-PIA, with L-PIA being 79 times more potent than D-PIA. In contrast to these effects, the adenosine receptor antagonist, theophylline, elicited a proconvulsant effect in doses from 15 to 60 mg/kg (i.p.). The effect of theophylline in reducing seizure threshold for pentylenetetrazol peaked at 30 mg/kg, a dose which reduced the seizure threshold by approx. 27%. Support for the involvement of recognition sites for adenosine in the observed modulation of seizure threshold was provided by the antagonism of the elevation of the seizure threshold for pentylenetetrazol induced by 2-ClAdo, by pretreatment with theophylline (5 mg/kg, i.v.). These findings provide support for the idea that endogenous adenosine may function as a regulator of seizure susceptibility.     

Effect of anticonvulsants on seizures developing in the course of daily administration of pentetrazol to rats

Progressive behavioral and electroencephalographic (EEG) changes were examined following daily administration of pentetrazol (PTZ) to rats. A dose (40 mg/kg/day i.p.) of PTZ which, on the first day, induced clonic convulsions with spike and wave complexes, over several days progressively increased its effect and finally induced ‘violent convulsions’ with EEG seizures of high frequency components. In rats showing these violent convulsions, the PTZ convulsive threshold was decreased and, even after a 4- to 10-month resting period, the violent convulsion was elicited with the same dose of PTZ. Trimethadione and phenobarbital in doses blocking clonic convulsion in normal rats, did not suppress these violent convulsions. Higher doses of the two drugs were necessary to suppress the violent convulsion. Diphenylhydantoin did not suppress either type of convulsions. It is suggested that the progressive development of seizure by PTZ is a kindling effect and that a part of the neuronal mechanisms by which the violent convulsion occurs is involved in the mechanisms underlying the clonic convulsion.     

Effect of Centella asiatica on pentylenetetrazole-induced kindling,cognition and oxidative stress in rats

Cognitive impairment in epileptics may be a consequence of the epileptogenic process as well as antiepileptic medication. Thus, there is a need for drugs, which can suppress epileptogenesis as well as prevent cognitive impairment. In the present study, the effect of aqueous extract of Centella asiatica (CA) (100 and 300 mg/kg), an Indian medicinal plant known to possess antiepileptic, cognitive-enhancing and antioxidant property, was evaluated on the course of kindling development, kindling-induced learning deficit and oxidative stress markers in pentylenetetrazole (PTZ) kindled rats. Male Wistar rats were injected PTZ (30 mg/kg ip) once every alternate day (48+/-2 h) until the development of the kindling. Passive avoidance test and spontaneous locomotor activity were carried out 24 and 48 h after the last administration of PTZ, while the oxidative stress parameters (malondialdehyde [MDA] and glutathione) were carried out in the whole brain upon completion of the behavioral assessment. The administration of CA (300 mg/kg orally) decreased the PTZ-kindled seizures and showed improvement in the learning deficit induced by PTZ kindling as evidenced by decreased seizure score and increased latencies in passive avoidance behavior. However, low dose of the CA (100 mg/kg) showed improvement only in the learning deficit due to the kindling and failed to improve the seizure score. The findings suggest the potential of aqueous extract of CA as adjuvant to antiepileptic drugs with an added advantage of preventing cognitive impairment.     

Pharmacological and genetic manipulation of kappa opioid receptors: effects on cocaine- and pentylenetetrazol-induced convulsions and seizure kindling

The present study used pharmacological and gene ablation techniques to examine the involvement of kappa opioid receptors (KOPr) in modulating the convulsant effects of two mechanistically different drugs: cocaine and pentylenetetrazol (PTZ; GABA-A receptor antagonist) in mice. Systemic administration of the selective KOPr-1 agonist, U69593 (0.16-0.6mg/kg; s.c.), failed to modify cocaine-evoked convulsions or cocaine kindling. Similarly, no alteration in responsiveness to cocaine was observed in wild-type mice that received the selective KOPr-1 antagonist, nor-binaltorphimine (nor-BNI; 5mg/kg) or in mice lacking the gene encoding KOPr-1. In contrast to cocaine, U69593 attenuated the seizures induced by acute or repeated PTZ administration. Nor-BNI decreased the threshold for PTZ-evoked seizures and increased seizure incidence during the initial induction of kindling relative to controls. Decreased thresholds for PTZ-induced seizures were also observed in KOPr-1 knock out mice. Together, these data demonstrate an involvement of endogenous KOPr systems in modulating vulnerability to the convulsant effects of PTZ but not cocaine. Furthermore, they demonstrate that KOPr-1 activation protects against acute and kindled seizures induced by this convulsant. Finally, the results of our study suggest that KOPr-1 antagonists will not have therapeutic utility against cocaine-induced seizures, while they may prove beneficial in attenuating several actions of cocaine that have been linked to its abuse.     

NAALADase (GCP II) inhibition prevents cocaine-kindled seizures

The prediction that inhibition of NAALADase, an enzyme catalyzing the cleavage of glutamate from N-acetyl-aspartyl-glutamate, would produce antiepileptogenic effects against cocaine was tested. Cocaine kindled seizures were developed in male, Swiss-Webster mice by daily administration of 60 mg/kg cocaine for 5 days. The NAALADase inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) produced dose-dependent protection (10-100 mg/kg) against both the development of seizure kindling and the occurrence of seizures during the kindling process without observable behavioral side-effects. It is not likely that 2-PMPA produced protection against cocaine kindling by altering the potency of the convulsant stimulus as daily administration of 2-PMPA did not alter the convulsant thresholds for cocaine. Lower daily doses of cocaine (40 mg/kg) did not increase the incidence of seizures but produced kindling, as evidenced by the increase in seizure susceptibility when mice were probed with a higher dose of cocaine. 2-PMPA was also effective in preventing the development of sensitization to this covert kindling process. In contrast to its efficacy against cocaine kindled seizures, 2-PMPA failed to attenuate the convulsions engendered by acute challenges with pentylenetetrazole, bicuculline, N-methyl-D-aspartate, maximal electroshock or cocaine. Similarly, acutely-administered 2-PMPA did not block cocaine seizures in fully-kindled mice. NAALADase inhibition thus provides a novel means of attenuating the development of cocaine seizure kindling.     

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.     

MK-801 prevents chemical kindling induced by pentylenetetrazol in rats.

The repeated administration of pentylenetetrazol (PTZ) at a subconvulsant dose (30 mg/kg i.p., three times a week for nine weeks) produced kindling in 90% of rats under treatment. Pretreatment with the N-methyl-D-aspartate receptor antagonist, MK-801 (1 mg/kg i.p., 40 min before PTZ), prevented the behavioral manifestation (i.e. motor seizures) as well as the development of kindling. In fact, convulsions were not observed in rats pretreated with MK-801 either during the chronic PTZ administration or when challenged with PTZ three and 10 days after completion of the chronic treatment. The results suggest an involvement of excitatory amino acid neurotransmission in PTZ kindling.     

Tolerance to the anti-pentylenetetrazole effects of diazepam in the mouse

The protective effects of acute and chronic diazepam administration (4 mg/kg) against seizures induced by pentylenetetrazole (PTZ) and picrotoxin were investigated. Considering the incidence of tonic-clonic convulsions, tolerance to the protective effects of diazepam was evident by day 5 if the mice were challenged with PTZ (120 mg/kg), by day 10 if the challenge was picrotoxin (8 mg/kg) and by day 20 if the challenge was PTZ (105 mg/kg). Diazepam retained its protective effects against tonic-clonic convulsions induced by PTZ (90 and 60 mg/kg) for 45 days, but the incidence of myoclonic jerks revealed tolerance after 5 days.     

Effects of sildenafil on pentylenetetrazol-induced convulsions in mice and amygdala-kindled seizures in rats

Sildenafil is the first marketed phosphodiesterase 5 inhibitor for the treatment of erectile dysfunction and recently, for pulmonary hypertension. While the treatment was found to be highly effective, several adverse effects are associated with this compound. Among numerous central nervous system-related untoward effects, proconvulsant activity was reported. The purpose of this study was to assess the effect of sildenafil on seizure threshold in rodents. Two seizure models/tests were used: the timed intravenous (iv) pentylenetetrazol (PTZ) infusion test in mice and the amygdala-kindling model in rats. Sildenafil was administered intraperitoneally 30 min before induction of seizures. In the iv PTZ paradigm, the first myoclonic twitch, generalized clonus with loss of the righting reflex, and forelimb tonus were recorded. In the amygdala-kindling model in rats, the following parameters were analyzed: threshold for induction of epileptiform discharges in the stimulated amygdala (afterdischarge threshold, ADT), seizure severity, seizure duration, and afterdischarge duration. Sildenafil (dosage range of 5–40 mg/kg) did not significantly affect the threshold for myoclonic twitches in the timed iv PTZ infusion test in mice but significantly decreased the threshold for clonic seizures at a dose of 20 mg/kg. Sildenafil at all doses tested neither significantly influenced the focal seizure threshold in the amygdala-kindling model of epilepsy in rats nor influenced seizure severity. Sildenafil significantly shortened afterdischarge duration and seizure duration recorded at the ADT current, indicative of a weak anticonvulsant activity. Our results show that sildenafil may have both pro- and anticonvulsant activity, which depends on the experimental model of epilepsy, on animal species and the dose of sildenafil. Based on these data and in view of the clinical observations, sildenafil should be used in patients suffering from epilepsy with caution and only based on a careful individual risk/benefit evaluation.     

Lamotrigine Decreased Hippocampal Damage and Improved Vascular Risk Markers in a Rat Model of Pentylenetetrazole Induced Kindling Seizure

Various antiepileptic drugs (AEDs) especially enzyme-inducing AEDs might be associated with increased vascular risk, through impairment of the endogenous antioxidative ability which may trigger oxygen-dependent tissue injury. Lamotrigine (LTG) a non-enzyme-inducing AED has scarce information regarding its effects on oxidative stress. The present study aimed to study the possible modulation of vascular risk factors of epileptogenesis by LTG, in a rat model of kindling seizure induced by pentylenetetrazole (PTZ). Four groups of male Wister rats were used; vehicle control group, PTZ group (alternate day PTZ, 30 mg/kg, i.p), LTG/PTZ group (LTG 20 mg/kg/day p.o and alternate day PTZ) and LTG group. The study period was 5 weeks. Lipoproteins and total homocysteine (tHcy), malondialdehyde (MDA) and reduced glutathione (GSH) were measured. Aortic endothelial function study and histopathological examination of the rats'' brains, aortas and coronaries were conducted. Serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C), tHcy, MDA, GSH levels were significantly higher in epileptic rats than normal controls rats. A decrease in HDL-cholesterol with high atherosclerotic index was also demonstrated. The administration of LTG improved the PTZ-kindled seizures. It produced a significant decrease in TC, TG and LDL-cholesterol, MDA, aortic GSH and increase in HDL-cholesterol with no significant effect on serum GSH and tHcy levels. LTG improved endothelium-dependent relaxation, decreased hippocampal neurodegenerative changes and atherosclerotic changes of aortas and coronaries. LTG decreased seizures severity, hippocampal damage and improved vascular risk markers in this rat model of kindling seizures.     

组氨酸，一种组胺的前体对戊四唑诱发大鼠癫痫的作用

目的:研究和阐明中枢组胺对戊四唑(PTZ诱发大鼠点燃癫痫的作用机制.方法:隔日腹腔内注射亚惊厥剂量的PTZ 35 mg/kg诱发化学点燃癫痫,直至癫痫发作级别为4—5级.观察每次PTZ注射后30分钟内大鼠的行为变化.结果:在癫痫形成过程中,腹腔内注射组氨酸(200,500mg/kg),一种组胺的前体,剂量依赖性地延缓出现肌性痉挛和阵挛性癫痫全身性发作的反应潜时和抑制癫痫发作的级别.在癫痫模型形成后点燃激发过程中,组氨酸(500,1000mg/kg)和组胺H_3受体阻断剂4-[4′-(环己氨基硫代甲酰基哌啶)]-4H-咪唑(10,20μg)也分别表现出了明显的抗癫痫作用(2.6±0.4,2.2±0.3),(2.8±0.6,2.1±0.5).组氨酸的作用可被4-[4′-(环已氨基硫代甲酰基哌啶)]-4H-咪唑(5μg)显著性增强,却被选择性组氨酸脱羧酶抑制剂α-氟甲基组胺酸(20μg)和H_1受体拮抗剂美吡拉敏(2,5mg/kg)剂量依赖性、显著性地抑制.另外,H_2受体拮抗剂卓兰替丁即使在10mg/kg剂量下也无明显的对抗作用.结论:内源性组胺在对抗阵挛性癫痫全身性发作中起到了较重要的作用,其作用主要与突触前膜H_3受体与突触后膜H_1受体相关.     

Anticonvulsant and antioxidant actions of trimetazidine in pentylenetetrazole-induced kindling model in mice

The present study was carried out to investigate the effect of trimetazidine on the course of pentylenetetrazole (PTZ)-induced chemical kindling and oxidative stress markers in PTZ-kindled mice. Kindling was induced by repeated injections of a subconvulsive dose of PTZ (30?mg?kg, i.p.) on alternate days for 5?weeks or until stage 4 of the seizure score was evoked on three consecutive administrations. Trimetazidine was administered daily in three doses (5, 10 and 20?mg/kg) per orally (p.o.) along with alternate-day PTZ. Following PTZ kindling, oxidative stress parameters, i.e. levels of malondialdehyde (MDA) and reduced glutathione (GSH), were assessed in isolated homogenized whole brain tissue. The results showed that PTZ treatment progressively increased the seizure score in control mice. Biochemical analysis revealed a significant increase in MDA levels and decreased GSH levels in the brain homogenate of PTZ-kindled mice. Daily treatment with trimetazidine in doses of 10 and 20?mg/kg significantly decreased the PTZ-induced seizure score. However, a low dose of trimetazidine (5?mg/kg) failed to improve the seizure score. Pretreatment of trimetazidine in all doses showed an ameliorating effect on biochemical alteration induced by PTZ treatment. The results of the present study indicate the potential anticonvulsant activity of trimetazidine against PTZ-induced kindling in mice.     

Repeated administration of subconvulsant doses of GABA antagonist drugs

The effect on monoamine-mediated behaviour of repeated daily subconvulsive doses of the GABA antagonist drugs pentylenetetrazol (PTZ) (30 mg/kg for 8 days), picrotoxin (5 mg/kg for 4 days) and bicuculline (3.5 mg/kg for 16 days) was investigated. None of the drugs, administered chronically, increased behavioural responses to the 5-hydroxytryptamine agonist quipazine (25 mg/kg), and neither picrotoxin nor bicuculline altered the locomotor response to the dopamine agonist apomorphine (AP) (0.1 mg/kg). By contrast, repeated doses of PTZ increased the locomotor response to AP, and also increased circling responses to both AP (0.5 mg/kg) and methamphetamine (2.0 mg/kg) in unilateral nigrostriatal-lesioned rats.     

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.     

Influence of low dietary histamine on seizure development of chemical kindling induced by pentylenetetrazol in rats

Aim: To determine the role of dietary low histamine on the seizure development of pentylenetetrazol (PTZ)-induced kindling in rats. Methods: After 14d of feeding on a low histamine diet (LH, containing 0.145μmol/g of histamine), the rats were chemically kindled by repeated intraperitoneal injection of a subconvulsant dose of PTZ (35mg/kg) once every 48h, and seizure activity of kindling was recorded for 30min. Histamine in brain samples was analyzed using a high performance liquid chromatography system with a fluorescence spectrofluorometer. Results:The LH diet induced an increase in seizure response (seizure susceptibility) to the first trial of PTZ, and resulted in facilitation of subsequent PTZ kindling process (seizure development). The histamine levels in the cortex, hippocampus, and hypothalamus of LH-treated rats decreased significantly and these changes correlated well with seizure behavior (r=0.875,0.651, and 0.796, respectively). In addition, chronic kindled seizures resulted in a significant increase of the histamine content in the cortex and hypothalamus in the LH-fed groups. Conclusion: These findings indicate that the histamine in daily food could influence the brain histaminergic function, and play an important role in regulating seizure susceptibility.