γ-Hydroxybutyric acid-induced absence seizures in GluR2 null mutant mice

In this electrophysiological study, we examined the susceptibility of GluR2 mutant null mice to absence seizures in comparison with wild-type controls. The prodrug of (GHB), γ-butyrolactone (GBL) was given systemically to induce the absence seizures. We also tested the severity and duration of the seizure activity in this model. The results showed that the latency from GBL administration to onset of seizure was significantly prolonged in GluR2^−/− mice when compared to GluR2^+/+ mice. The duration of spike-and-wave discharges (SWD) was also significantly decreased in the GluR2^−/− mice. Ninety minutes following GBL administration, wild-type animals continued to exhibit intermittent SWD bursts while GluR2^−/− mice had returned to baseline. These data suggest that the GluR2 subunit may be involved in the initiation and maintenance of absence seizures induced by GBL.     

Alteration of GLUR2 expression in the rat brain following absence seizures induced by gamma-hydroxybutyric acid

We explored the involvement of the glutamate receptor subunit B (GluR2) in the mechanism of absence seizures induced by gamma-hydroxybutyric acid (GHB). The expression and distribution of GluR2 protein in rat brain were examined during and after GHB-induced absence seizures. The data indicate that GluR2 protein expression significantly decreases following the onset of absence seizures. The suppression of GluR2 expression was prolonged and it outlasted the duration of the continuous absence seizure activity. The alteration of GluR2 protein levels was accompanied by a re-distribution of GluR2 expression from laminae V to IV in cerebral cortex. We also analyzed the duration and latency of absence seizures induced by GHB 72 h following an initial GHB-induced absence seizure, a time when suppression of GluR2 protein was maximal. The second absence seizure was significantly more prolonged than the first. These data may indicate that the putative down-regulation of GluR2 following GHB-induced absence seizure could have contributed to the potentiation of subsequent seizures in animals. A related hypothesis posed by the data is that down-regulation of GluR2 is involved in the mechanisms of the maintenance of recurrent absence seizure activity once it is initiated and therefore, may contribute to the chronicity of seizures in absence epilepsy.     

Altered thalamocortical rhythmicity in Ca(v)2.3-deficient mice

Voltage-gated calcium channels (VGCCs) are key regulators of neuronal excitability and important factors in epileptogenesis and neurodegeneration. Recent findings suggest a novel, important proictogenic and proneuroapoptotic role of the Ca_v2.3 E/R-type VGCCs in convulsive generalized tonic–clonic and hippocampal seizures. Though Ca_v2.3 is also expressed in key structures of the thalamocortical circuitry, their functional relevance in non-convulsive absence seizure activity remains unknown. To this end, we investigated absence specific spike–wave discharge (SWD) susceptibility in control and Ca_v2.3-deficient mice by systemic administration of γ-hydroxybutyrolactone (GBL, 70 mg/kg i.p.), followed by electrocorticographic radiotelemetric recordings, behavioral analysis and histomorphological characterization. Based on motoric studies, SWD and power-spectrum density (PSD) analysis, our results demonstrate that Ca_v2.3^−/− mice exhibit increased absence seizure susceptibility and altered absence seizure architecture compared to control animals. This study provides evidence for the first time that Ca_v2.3 E/R-type Ca²⁺ channels are important in modulating thalamocortical hyperoscillation exerting anti-epileptogenic effects in non-convulsive absence seizures.     

Corticothalamic modulation during absence seizures in rats: a functional MRI assessment

PURPOSE: Functional magnetic resonance imaging (fMRI) was used to identify areas of brain activation during absence seizures in an awake animal model. METHODS: Blood-oxygenation-level-dependent (BOLD) fMRI in the brain was measured by using T2*-weighted echo planar imaging at 4.7 Tesla. BOLD imaging was performed before, during, and after absence seizure induction by using gamma-butyrolactone (GBL; 200 mg/kg, intraperitoneal). RESULTS: The corticothalamic circuitry, critical for spike-wave discharge (SWD) formation in absence seizure, showed robust BOLD signal changes after GBL administration, consistent with EEG recordings in the same animals. Predominantly positive BOLD changes occurred in the thalamus. Sensory and parietal cortices showed mixed positive and negative BOLD changes, whereas temporal and motor cortices showed only negative BOLD changes. CONCLUSIONS: With the BOLD fMRI technique, we demonstrated signal changes in brain areas that have been shown, with electrophysiology experiments, to be important for generating and maintaining the SWDs that characterize absence seizures. These results corroborate previous findings from lesion and electrophysiological experiments and show the technical feasibility of noninvasively imaging absence seizures in fully conscious rodents.     

Aggravation of absence seizures by carbamazepine in a genetic rat model does not induce neuronal c-Fos activation

The mechanisms underlying carbamazepine aggravation of absence seizures are uncertain but are thought to involve enhancement of neuronal activity within the thalamocortical circuitry. We used c-Fos immunohistochemistry (cFos-ir) to examine patterns of neuronal activation and the relationship to seizure expression following administration of carbamazepine in a rat model of absence epilepsy (Genetic Absence Epilepsy Rats of Strasbourg, GAERS). Female ovariectomized GAERS implanted with extradural EEG electrodes received either 20 mg/kg carbamazepine or vehicle IP. Seizure expression was quantified by measuring the total number and duration of spike-wave discharges (SWD) and with the individual burst discharge lengths over a 90-minute EEG. This was correlated with cFos-ir in thalamocortical slices from rats killed 180 minutes after carbamazepine administration. Carbamazepine-treated rats (n = 5) had a significantly greater total duration of SWD than vehicle-treated rats (17.9% versus 8.8%, P = 0.04). Despite this aggravation of seizures, the level of cFos-ir did not differ between the treatment groups. A positive correlation was found between cFos-ir in the reticularis thalami (Rt) and the total seizure duration (R = 0.66, P = 0.04) and mean burst length (R = 0.68, P = 0.03) but not total number of seizures. The lack of difference in cFos activation patterns between carbamazepine and vehicle-treated animals suggests that the mechanism for carbamazepine aggravation of absence seizures may not involve neuronal activation but rather enhanced neuronal synchronization. The association between increased neuronal activation in the Rt and seizure burden in GAERS provides further support for the critical role of this structure in the maintenance, but not initiation, of absence seizure activity.     

An anticonvulsant profile of the ketogenic diet in the rat

The present study was designed to evaluate the anticonvulsant effects of a high-fat ketogenic diet (KD) in rats. Animals were maintained on one of four experimental diets: (1) calorie-restricted ketogenic (KCR); (2) calorie-restricted normal (NCR); (3) ad libitum ketogenic (KAL); or (4) ad libitum normal (NAL). The calorie-restricted diets were fed in quantities such that they were calorically equivalent. All animals began diet treatment at age P37 and each was subjected to one of five chemically-induced seizure tests: bicuculline (BIC; s.c.), picrotoxin (PIC; s.c.), kainate (KA, i.p. or s.c.) and γ-butyrolactone (GBL, i.p.), strychnine (s.c.). Bipolar epidural electrodes were implanted under ketamine/xylazine anesthesia to permit recording the spike and wave discharges (SWD) characteristic of electroencephalograms during absence seizures. Ketonemia was assayed by measuring blood levels of β-hydroxybutyrate (BHB) spectrophotometrically prior to induction of seizures in each experiment. Animals fed ketogenic diets (i.e. either calorie restricted or ad libitum) exhibited greater blood levels of BHB compared to control groups. Seizure results show that treatment with a KD: (1) reduced the incidence of bicuculline-induced convulsions; (2) diminished the number of picrotoxin-induced seizures (KCR group only); (3) increased latency to GBL-induced SWD and reduced both the number and duration of SWD; but (4) conferred no protection from strychnine-induced seizures; and (5) made KA-induced seizures more severe. Together these results indicate a spectrum of anticonvulsant action for the KD in rats that includes threshold seizures induced via GABA receptors (BIC, PIC, GBL) but not those induced at glycine (strychnine) or the KA-subclass of glutamate receptors. Uniquely, the KD is the only treatment described that protects against both convulsive and non-convulsive (absence) seizures in rats.     

Mutation of NMDA receptor subunit epsilon 1: effects on audiogenic-like seizures induced by electrical stimulation of the inferior colliculus in mice

It has been shown that the N-methyl-D-asparate (NMDA) receptor in the inferior colliculus is involved in the induction of audiogenic seizures (AGS). In the present study we examined audiogenic-like seizure susceptibility in GluR epsilon 1 null KO adult mice (n=32) and wild-type adult mice (n=28) by electrically stimulating the inferior colliculus (IC). Threshold current intensities of the GluR epsilon 1 KO mice for wild running, clonic and tonic seizures were higher than those of wild-type mice. In addition, the incidence rates of each seizure syndrome in GluR epsilon 1 KO mice were lower than in wild-type mice at each current intensity. These results show that GluR epsilon 1 KO mice were more resistant to audiogenic-like seizures induced by stimulating the IC. Thus, our findings suggest that the GluR epsilon 1 subunit plays an important role in regulating AGS.     

gamma-Hydroxybutyric acid-induced seizures bear no relation to core temperature

The hypothesis that the absencelike seizures induced by gamma-hydroxybutyrate (GHB) are secondary to the effect of this drug on body temperature was tested using the prodrug of GHB, gamma-butyrolactone (GBL). Dosages of GBL less than 400 mg/kg produced a consistent profound hypothermia associated with bilaterally synchronous spike-wave discharges (SWD), whereas higher doses were associated with a more complex effect on core temperature associated with an EEG pattern of burst suppression. The threshold dose for the hypothermia and SWD was the same, but the temperature changes occurred later and lasted longer than the SWD induced by GHB. Rats aged less than 28 days were less sensitive to the hypothermia but more sensitive to the SWD produced by GHB than adult animals. The antiepileptic drug (AED) ethosuximide (ESM), known to attenuate GHB-induced SWD did so, but had no effect on the hypothermia, whereas GHB-induced hypothermia, but not SWD, was blocked by raising the ambient temperature from 26 degrees to 32 degrees C. These data do not support the hypothesis that GHB-induced absencelike seizure activity is a result of the hypothermia produced by this drug. Rather they suggest that the SWD and hypothermia are caused by separate, independent mechanisms.     

NMDA Preconditioning Attenuates Cortical and Hippocampal Seizures Induced by Intracerebroventricular Quinolinic Acid Infusion

Searching for new therapeutic strategies through modulation of glutamatergic transmission using effective neuroprotective agents is essential. Glutamatergic excitotoxicity is a common factor to neurodegenerative diseases and acute events such as cerebral ischemia, traumatic brain injury, and epilepsy. This study aimed to evaluate behavioral and electroencephalographic (EEG) responses of mice cerebral cortex and hippocampus to subconvulsant and convulsant application of NMDA and quinolinic acid (QA), respectively. Moreover, it aimed to evaluate if EEG responses may be related to the neuroprotective effects of NMDA. Mice were preconditioned with NMDA (75 mg/kg, i.p.) and EEG recordings were performed for 30 min. One day later, QA was injected (36.8 nmol/site) and EEG recordings were performed during 10 min. EEG analysis demonstrated NMDA preconditioning promotes spike-wave discharges (SWDs), but it does not display behavioral manifestation of seizures. Animals that were protected by NMDA preconditioning against QA-induced behavioral seizures, presented higher number of SWD after NMDA administration, in comparison to animals preconditioned with NMDA that did display behavioral seizures after QA infusion. No differences were observed in latency for the first seizure or duration of seizures. EEG recordings after QA infusion demonstrated there were no differences in the number of SWD, latency for the first seizure or duration of seizures in animals pretreated with saline or in animals preconditioned by NMDA that received QA. A negative correlation was identified between the number of NMDA-induced SWD and QA-induced seizures severity. These results suggest a higher activation during NMDA preconditioning diminishes mice probability to display behavioral seizures after QA infusion.     

Effects of carisbamate (RWJ-333369) in two models of genetically determined generalized epilepsy, the GAERS and the audiogenic Wistar AS

PURPOSE: The antiepileptic effects of carisbamate were assessed in two models of genetic epilepsy, a model of absence seizures, the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) and a model of convulsive seizures, the Wistar Audiogenic Sensitive (AS) rat. METHODS: GAERS were equipped with four cortical electrodes over the frontoparietal cortex and the duration of spike-and-wave discharges (SWD) was recorded for 20-120 min. In Wistar AS, the occurrence of, latency to, and duration of wild running and tonic seizures were recorded. RESULTS: In GAERS, carisbamate (10, 30, and 60 mg/kg) dose dependently reduced the expression of SWD that totally disappeared at the two highest doses by 40 min after injection. SWD duration returned to control levels by 100 min after the injection of 30 mg/kg carisbamate while SWDs were totally suppressed for 120 min after the injection of 60 mg/kg carisbamate. In Wistar AS, 10 mg/kg carisbamate increased the latency to the first running episode and induced the occurrence of a second running episode in three of eight rats. This episode was not present in untreated rats and was indicative of decreased sensitivity to the stimulus. This dose of carisbamate increased by 327% the latency to the tonic seizure that still occurred in the six of eight rats studied. At 20 and 30 mg/kg, no rats exhibited any wild running or tonic seizure. CONCLUSIONS: The present results support the broad spectrum of antiepileptic activity of carisbamate confirming its efficacy in animal models of primary generalized seizures of both tonic-clonic and of the absence type.     

Amygdala-kindled and pentylenetetrazole-induced seizures in glutamate transporter GLAST-deficient mice

The glutamatergic system has been shown to be important for the induction of epileptiform activity and the development of epileptogenesis. To investigate the role of the astroglial glutamate transporter GLAST in epileptogenesis, we examined amygdala (AM)-kindled and pentylenetetrazole (PTZ)-induced seizures in GLAST-deficient mice (GLAST(-/-)) and compared them to those observed in wild-type mice (GLAST(+/+)) and maternal C57Black6/J (C57) mice. AM-kindling resulted in no significant differences in afterdischarge threshold or in the seizure responses induced by first stimulation between these groups. In addition, although no significant differences were seen in kindled seizure development, the generalized seizure duration of AM-kindled seizures in GLAST(-/-) mice was significantly prolonged (approximately 35%) compared with that of C57 mice. Furthermore, GLAST(-/-) mice showed more severe stages of PTZ-induced seizures than GLAST(+/+) mice, and the latency to the onset of seizures was significantly shorter for the mutant mice. These results indicate that GLAST is one of factors determining seizure susceptibility.     

Modulation of absence seizures by the GABA(A) receptor: a critical rolefor metabotropic glutamate receptor 4 (mGluR4).

Experimental absence seizures are associated with perturbations in the presynaptic release of GABA and glutamate within thalamocortical circuitry. The release of both glutamate and GABA is regulated by group III metabotropic glutamate receptors (mGluRs). Therefore, we examined the susceptibility of mice lacking the mGluR4 subtype of mGluR (mGluR4(-/-)) versus their wild-type controls (mGluR4(+/+)) to absence seizures induced either by gamma-hydroxybutyrate (GHB) or the GABA(B) agonist (-) baclofen or by low doses of the GABA(A) receptor (GABA(A)R) antagonists pentylenetetrazole, bicuculline, or picrotoxin. There was no difference between mGluR4(-/-) and mGluR4(+/+) mice in threshold to absence seizures induced by either GHB or (-) baclofen. In contrast, the mGluR4(-/-) mice were markedly resistant to absence seizures induced by low doses of GABA(A)R antagonists. No differences were observed between mGluR4(-/-) and mGluR4(+/+) mice in threshold to clonic or tonic seizures induced by higher doses of GABA(A)R antagonists, strychnine, or electroshock, indicating that seizure resistance in the mGluR4(-/-) mice was restricted solely to absence seizures. The resistance of mGluR4(-/-) mice to absence seizures induced by GABA(A)R antagonists was mimicked by bilateral administration of a mGluR4 antagonist into the nucleus reticularis thalami (nRT) of mGluR4(+/+) mice. Conversely, intra-nRT administration of a mGluR4 agonist in mGluR4(+/+) mice exacerbated GABA(A)R-induced absence seizures. These data indicate that the presence of mGluR4 within nRT is critical to GABAergic modulation of thalamocortical synchronization in normal and pathological states, such as generalized absence epilepsy.     

Differential actions of NPY on seizure modulation via Y1 and Y2 receptors: evidence from receptor knockout mice

PURPOSE: Neuropeptide Y (NPY) has been shown to modulate seizure activities. To provide further understanding of the involvement of two of the most abundantly expressed NPY receptors, Y1 and Y2, we assessed the effect of Y1 and Y2 gene deletion on systemic kainic acid-induced seizures. We also examined the effect of rAAV-mediated hippocampal NPY overexpression on seizure susceptibility in these receptor knockout mice. METHODS: Recombinant adeno-associated viral vector overexpressing NPY (rAAV-NPY) or an empty vector control (rAAV-Empty) was injected into the hippocampus of adult C57BL/6-129/SvJ wild-type male mice and mice deficient of Y1 or Y2 receptors on the same background. Four weeks after vector injection, mice were subjected to systemic kainic acid-induced seizures, and the seizure behaviors were scored. RESULTS: The rAAV-mediated hippocampal overexpression of NPY led to a twofold reduction in seizures induced by systemic kainic acid in wild-type mice and Y1 receptor knockout mice but not in mice deficient of Y2 receptors. A differential action by the receptors was observed in the seizure-induced mortality rate, with increased fatality in Y2-/- mice. In addition, although NPY overexpression did not significantly affect the mortality rate in Y2-/- and wild-type mice, it abolished KA-induced mortality in Y1-/-mice. CONCLUSIONS: This study shows for the first time an altered susceptibility to chemically induced seizures in Y1 and Y2 knockout mice and demonstrates a differential seizure modulation mediated by these receptors via a genetic approach.     

The influence of gender on the aggravation of absence seizures by carbamazepine in the low-dose pentylenetetrazol rat model.

OBJECTIVES: To determine whether carbamazepine (CBZ) aggravates absence seizures in the low-dose pentylenetetrazol (PTZ) rat model in both male and female animals, and investigate for gender differences. METHODS: Inbred Sprague-Dawley rats were implanted with EEG electrodes. Seven days later PTZ (20 mg/kg, i.p.) was administered following pre-treatment with vehicle or CBZ (20 mg/kg, i.p.) and the occurrence of spike-and-wave discharges (SWDs) on the EEG quantified. RESULTS: The cumulative SWD for 90-minute post-PTZ was higher in the CBZ versus vehicle pre-treatment arm for both female (mean 110 seconds vs. 62 seconds; P = 0.03) and male (mean 89 seconds vs. 60 seconds; P = 0.03) rats. The increase in SWD duration in the CBZ arm was greater in female rats for the first five 15-minute intervals, but none attained statistical significance (P > 0.05). CBZ pre-treatment resulted in reductions in both SWD frequency (Hz) (male, P = 0.003; female, P < 0.0001) and latency to onset of SWD (male, P = 0.002). The frequency of SWD in CBZ pre-treated rats was lower in females (5.8 Hz vs. 6.1 Hz, P = 0.002) as was the decrease in the SWD burst duration following CBZ versus vehicle pre-treatment (-0.05 seconds vs. -0.25 seconds, P = 0.046). CONCLUSIONS: CBZ consistently aggravates absence seizures in the low-dose PTZ model in both female and male rats. However, while some gender differences were found, the results failed to support the hypothesis that females are significantly more susceptible to aggravation of the number or duration of absence seizures by CBZ.     

γ-Hydroxybutyrate Model of Generalized Absence Seizures: Further Characterization and Comparison with Other Absence Models

gamma-Hydroxybutyrate (GHB) produces a constellation of EEG and behavioral events that respond selectively to antiabsence antiepileptic drugs. The GHB-induced seizure was quantitated in the presence of three other absence seizure models: pentylenetetrazole, systemic penicillin, and the flash evoked afterdischarge (FEAD). Penicillin and pentylenetetrazole produced a significant prolongation of GHB-induced seizure in a dose-dependent fashion. This potentiation of GHB seizure was observed when these compounds were given either before administration of gamma-butyrolactone (GBL), the prodrug of GHB, or at the onset of GHB-induced seizure. Photic stimulation given in a manner to produce FEAD also resulted in a significant prolongation of GHB-induced seizure. All of these maneuvers lowered the threshold to GHB seizure, but none interfered with the brain kinetics of GHB in the animals treated with GBL. Ethosuximide pretreatment significantly shortened the GHB seizure and overcame the potentiating effect of penicillin and pentylenetetrazole in this model. These data confirm the GHB-treated animal as a model of generalized absence seizure. The GHB model meets appropriate criteria for an absence seizure model and compares favorably with other models of absence currently in use.     

Effect of gamma-crotonolactone in experimental models of generalized absence seizures

The effect of the unsaturated lactone, gamma-crotonolactone (GCL), against spike wave discharges (SWD) in two pharmacological models of generalized absence seizures in rat was investigated. The models used were the gamma-hydroxybutyrate (GHB) model and the low dose pentylenetetrazole model. GCL pretreatment resulted in a significant decrease in duration of SWD in both models. In addition, this compound reduced the ability of the agonist, muscimol, to enhance SWD duration in the GHB model and was effective in developing animals as well as in adult animals with GHB-induced SWD. These data suggest that GCL may be a useful tool in the study of basic mechanisms of SWD generation in experimental absence seizures.     

fMRI of generalized absence status epilepticus in conscious marmoset monkeys reveals corticothalamic activation

PURPOSE: A nonhuman primate model of generalized absence status epilepticus was developed for use in functional magnetic resonance imaging (fMRI) experiments to elucidate the brain mechanisms underlying this disorder. METHODS: Adult male marmoset monkeys (Callithrix jacchus) were treated with gamma-butyrolactone (GBL) to induce prolonged absence seizures, and the resulting spike-wave discharges (SWDs) were analyzed to determine the similarity to the 3-Hz SWDs that characterize the disorder. In addition, blood-oxygenation-level-dependent (BOLD) fMRI was measured at 4.7 Tesla after absence seizure induction with GBL. RESULTS: Electroencephalographic recordings during imaging showed 3-Hz SWDs typical of human absence seizures. This synchronized EEG pattern started within 15 to 20 min of drug administration and persisted for >60 min. In addition, pretreatment with the antiepileptic drug, ethosuximide (ESM), blocked the behavioral and EEG changes caused by GBL. Changes in BOLD signal intensity in the thalamus and sensorimotor cortex correlated with the onset of 3-Hz SWDs. The change in BOLD signal intensity was bilateral but heterogeneous, affecting some brain areas more than others. No significant negative BOLD changes were seen. CONCLUSIONS: The BOLD fMRI data obtained in this marmoset monkey model of absence status epilepticus shows activation within the thalamus and cortex.     

Effects of piracetam alone and in combination with antiepileptic drugs in rodent seizure models

Summary. The nootropic drug piracetam was investigated in various experimental models of epilepsy. Generally, piracetam exhibits no or only moderate anticonvulsant properties against generalized tonic or clonic seizures. However, in many cases it did increase the anticonvulsant effectiveness of conventional antiepileptics, as shown in the maximal electroshock seizure (MES) threshold test, the traditional MES test or in DBA/2 mice. A pharmacokinetic interaction does not seem to be responsible for this effect. In lethargic mice, a model of absence seizures, piracetam significantly decreased the incidence and duration of spike-wave discharges. Furthermore, in the cobalt-induced focal epilepsy model piracetam reduced the number of spikes/min and in the hippocampal stimulation model it increased the anticonvulsant potency of phenobarbital and phenytoin after single and repeated administration. In conclusion, the well tolerated piracetam itself did not show marked anticonvulsant effects in most screening tests, however, its co-medication with antiepileptic drugs improved seizure protection in various models which may bear potential clinical significance.     

Effects of topiramate in two models of genetically determined generalized epilepsy,the GAERS and the Audiogenic Wistar AS

PURPOSE: The antiepileptic effects of topiramate (TPM) were assessed in two models of genetically determined generalized epilepsy. The model of nonconvulsive epilepsy used was a model of absence seizures, the GAERS (Genetic Absence Epilepsy Rat from Strasbourg); and the model of convulsive seizures was an audiogenic rat model, the Wistar Audiogenic Sensitive (AS) rat. METHODS: GAERS were equipped with four cortical electrodes over the frontoparietal cortex, and the duration of spike-and-wave discharges (SWDs) on the EEG was recorded for periods of 20 to 120 or 300 min. In Wistar AS, the occurrence of, latency to, and duration of one or two wild running episodes and tonic seizures were recorded. RESULTS: In the 16 GAERS studied, TPM (10, 30, and 60 mg/kg) dose-dependently reduced the expression of SWD that almost totally disappeared at the two highest doses between 40 and 120 min. SWD duration returned to control levels by 180 and 280 min after the injection of 30 and 60 mg/kg TPM, respectively. In Wistar AS, 10 mg/kg TPM induced the occurrence of a second running episode not present in control rats, indicative of a decrease in sensitivity of the rats to the stimulus and increased by 330% the latency to the tonic seizure that still occurred in the eight rats studied. At 30 and 60 mg/kg, the latency to wild running increased by 140%; the second running episode was suppressed in six and seven rats, respectively, whereas the tonic seizure occurred only in one of the eight rats studied at these two doses. CONCLUSIONS: These results support the broad spectrum of antiepileptic activity of TPM, confirming its efficacy in primary generalized seizures of both tonic-clonic and of the absence type.     

Lamotrigine ameliorates seizures and psychiatric comorbidity in a rat model of spontaneous absence epilepsy

Purpose: Lamotrigine (LTG) is an effective clinical treatment for epilepsy associated with absence seizures. However, the impact of LTG administration in studies employing various animal models of epilepsy remains controversial. This study aimed to clarify the outcomes of LTG treatment on absence seizures and comorbid anxiety and depression disorders in Long‐Evans rats with spontaneous spike‐wave discharges (SWDs). Methods: LTG (10 mg/kg) or water vehicle was chronically administered perorally to Long‐Evans rats (twice daily for 35 days). Cortical activities were recorded to assess the presence of SWDs. Five behavioral tests, including the open field (OF), elevated plus maze (EPM), sucrose consumption (SC), sucrose preference, and forced swimming (FS) tests, were performed after LTG/vehicle treatment. The behavioral indexes of these tests were designed to assess anxiety (OF and EPM tests), depression (SC and FS tests), and preference for hedonistic stimuli (sugar preference test). Key Findings: Total SWD duration, SWD number, and mean SWD duration were significantly decreased in rats that received 35‐day LTG treatment compared with rats that received vehicle treatment. Rats with spontaneous SWDs versus rats with no SWDs showed significant levels of anxiety and depression in the OF, EPM, and SC tests. Rats with SWDs also showed longer immobility in the FS test. However, the LTG‐treated group compared with the vehicle group presented with significantly lower manifestations of anxiety and depression in the OF, EPM, SC, and sucrose preference tests and shorter immobility in the FS test. Significance: The results of this study suggest that chronic LTG treatment can benefit patients with epilepsy via suppression of absence seizures and amelioration of comorbid anxiety and depression.