Neuroendocrine changes in the hypothalamic-neurohypophysial system in the Wistar audiogenic rat (WAR) strain submitted to audiogenic kindling.

The Wistar audiogenic rat (WAR) strain is used as an animal model of epilepsy, which when submitted to acute acoustic stimulus presents tonic-clonic seizures, mainly dependent on brainstem (mesencephalic) structures. However, when WARs are exposed to chronic acoustic stimuli (audiogenic kindling-AK), they usually present tonic-clonic seizures, followed by limbic seizures, after recruitment of forebrain structures such as the cortex, hippocampus and amygdala. Although some studies have reported that hypothalamic-hypophysis function is also altered in WAR through modulating vasopressin (AVP) and oxytocin (OXT) secretion, the role of these neuropeptides in epilepsy still is controversial. We analyzed the impact of AK and consequent activation of mesencephalic neurocircuits and the recruitment of forebrain limbic (LiR) sites on the hypothalamic-neurohypophysial system and expression of Avpr1a and Oxtr in these structures. At the end of the AK protocol, nine out of 18 WARs presented LiR. Increases in both plasma vasopressin and oxytocin levels were observed in WAR when compared to Wistar rats. These results were correlated with an increase in the expressions of heteronuclear (hn) and messenger (m) RNA for Oxt in the paraventricular nucleus (PVN) in WARs submitted to AK that presented LiR. In the paraventricular nucleus, the hnAvp and mAvp expressions increased in WARs with and without LiR, respectively. There were no significant differences in Avp and Oxt expression in supraoptic nuclei (SON). Also, there was a reduction in the Avpr1a expression in the central nucleus of the amygdala and frontal lobe in the WAR strain. In the inferior colliculus, Avpr1a expression was lower in WARs after AK, especially those without LiR. Our results indicate that both AK and LiR in WARs lead to changes in the hypothalamic-neurohypophysial system and its receptors, providing a new molecular basis to better understaind epilepsy.

Photoparoxysmal response in ADCK3 autosomal recessive ataxia: a case report and literature review.

Mutations in AarF domain-containing kinase 3 (ADCK3) are responsible for the most frequent form of hereditary coenzyme Q10 (CoQ10) deficiency (Q10 deficiency-4), which is mainly associated with autosomal recessive cerebellar ataxia type 2 (ARCA2). Clinical presentation is characterized by a variable degree of cerebellar atrophy and a broad spectrum of associated symptoms, including muscular involvement, movement disorders, neurosensory loss, cognitive impairment, psychiatric symptoms and epilepsy. In this report, we describe, for the first time, a case of photoparoxysmal response in a female patient with a mutation in ADCK3. Disease onset occurred in early childhood with gait ataxia, and mild-to-moderate degeneration. Seizures appeared at eight years and six months, occurring only during sleep. Photoparoxysmal response was observed at 14 years, almost concomitant with the genetic diagnosis (c.901C>T;c.589-3C>G) and the start of CoQ10 oral supplementation. A year later, disease progression slowed down, and photosensitivity was attenuated. A review of the literature is provided focusing on epileptic features of ADCK3-related disease as well as the physiopathology of photoparoxysmal response and supposed cerebellar involvement in photosensitivity. Moreover, the potential role of CoQ10 oral supplementation is discussed. Prospective studies on larger populations are needed to further understand these data.

Kcnj16 knockout produces audiogenic seizures in the Dahl salt-sensitive rat.

Kir5.1 is an inwardly rectifying potassium (Kir) channel subunit abundantly expressed in the kidney and brain. We previously established the physiologic consequences of a Kcnj16 (gene encoding Kir5.1) knockout in the Dahl salt-sensitive rat (SSKcnj16-/-), which caused electrolyte/pH dysregulation and high-salt diet-induced mortality. Since Kir channel gene mutations may alter neuronal excitability and are linked to human seizure disorders, we hypothesized that SSKcnj16-/- rats would exhibit neurological phenotypes, including increased susceptibility to seizures. SSKcnj16-/- rats exhibited increased light sensitivity (fMRI) and reproducible sound-induced tonic-clonic audiogenic seizures confirmed by electroencephalography. Repeated seizure induction altered behavior, exacerbated hypokalemia, and led to approximately 38% mortality in male SSKcnj16-/- rats. Dietary potassium supplementation did not prevent audiogenic seizures but mitigated hypokalemia and prevented mortality induced by repeated seizures. These results reveal a distinct, nonredundant role for Kir5.1 channels in the brain, introduce a rat model of audiogenic seizures, and suggest that yet-to-be identified mutations in Kcnj16 may cause or contribute to seizure disorders.

Alterations in brainstem auditory processing, the acoustic startle response and sensorimotor gating of startle in Wistar audiogenic rats (WAR), an animal model of reflex epilepsies.

While acute audiogenic seizures in response to acoustic stimulus appear as an alteration in sensory-motor processing in the brainstem, the repetition of the stimulus leads to the spread of epileptic activity to limbic structures. Here, we investigated whether animals of the Wistar Audiogenic Rat (WAR) strain, genetically selected by inbreeding for seizure susceptibility, would have alterations in their auditory response, assessed by the auditory brainstem responses (ABR) and sensory-motor gating, measured as pre-pulse inhibition (PPI), which could be related to their audiogenic seizures susceptibility or severity. We did not find differences between the amplitudes and latencies of ABR waves in response to clicks for WARs when compared to Wistars. Auditory gain and symmetry between ears were also similar. However, hearing thresholds in response to some tones were lower and amplitudes of wave II were larger in WARs. WARs had smaller acoustic startle reflex amplitudes and the percentages of startle inhibited by an acoustic prepulse were higher for WARs than for Wistars. However, no correlation was found between these alterations and brainstem-dependent seizure severity or limbic seizure frequency during audiogenic kindling. Our data show that while WARs present moderate alterations in primary auditory processing, the sensory motor gating measured in startle/PPI tests appears to be more drastically altered. The observed changes might be correlated with audiogenic seizure susceptibility but not seizures severity.

Localizing and lateralizing values of postictal behavioral impairments in epileptic rats.

Transient postictal behavioral impairments in patients with epilepsy provide clues to seizure localization, but no attempt has been made previously to study the localization/lateralization value of postseizure motor disturbances in experimental models of epilepsy. The present study investigated relation of postictal motor deficit to seizure localization in the rat model of sound-induced reflex epilepsy. Sound-induced motor seizures started with a focal brainstem seizure (running) and progressed to a secondarily generalized seizure. Depending on innate or acquired seizure susceptibility of rats, focal brainstem seizures secondarily generalized within the brainstem (brainstem-generalized seizures) or spread to the forebrain (focal or generalized forebrain seizures). All sound-induced seizures were followed by catalepsy and abnormal limb posturing. The duration of the postictal catalepsy and the pattern of the posture abnormality depended on brainstem or forebrain localization of secondarily generalized seizures. Brainstem-driven seizures induced long-lasting whole-body catalepsy and cataleptic limb posture in the postictal period. Secondary seizure generalization to the forebrain led to shortening postictal catalepsy and development of rigid limb posturing. Asymmetric limb posturing was always observed after focal forebrain seizures, and the postictal asymmetry was closely linked to ictal asymmetry of the earliest running seizure phase, predicting lateralization of the seizure-onset side. This is the first demonstration of circuit-specific postictal behavioral impairments and their localization and lateralization values in epileptic rats.

A case of epilepsy induced by eating or by visual stimuli of food made of minced meat.

We report a 34-year-old woman with eating epilepsy induced not only by eating but also seeing foods made of minced meat. In her early 20s of age, she started having simple partial seizures (SPS) as flashback and epigastric discomfort induced by particular foods. When she was 33 years old, she developed SPS, followed by secondarily generalized tonic-clonic seizure (sGTCS) provoked by eating a hot dog, and 6 months later, only seeing the video of dumpling. We performed video electroencephalogram (EEG) monitoring while she was seeing the video of soup dumpling, which most likely caused sGTCS. Ictal EEG showed rhythmic theta activity in the left frontal to mid-temporal area, followed by generalized seizure pattern. In this patient, seizures were provoked not only by eating particular foods but also by seeing these. This suggests a form of epilepsy involving visual stimuli.

The Wistar Audiogenic Rat (WAR) strain and its contributions to epileptology and related comorbidities: History and perspectives.

In the context of modeling epilepsy and neuropsychiatric comorbidities, we review the Wistar Audiogenic Rat (WAR), first introduced to the neuroscience international community more than 25years ago. The WAR strain is a genetically selected reflex model susceptible to audiogenic seizures (AS), acutely mimicking brainstem-dependent tonic-clonic seizures and chronically (by audiogenic kindling), temporal lobe epilepsy (TLE). Seminal neuroethological, electrophysiological, cellular, and molecular protocols support the WAR strain as a suitable and reliable animal model to study the complexity and emergent functions typical of epileptogenic networks. Furthermore, since epilepsy comorbidities have emerged as a hot topic in epilepsy research, we discuss the use of WARs in fields such as neuropsychiatry, memory and learning, neuroplasticity, neuroendocrinology, and cardio-respiratory autonomic regulation. Last, but not least, we propose that this strain be used in "omics" studies, as well as with the most advanced molecular and computational modeling techniques. Collectively, pioneering and recent findings reinforce the complexity associated with WAR alterations, consequent to the combination of their genetically-dependent background and seizure profile. To add to previous studies, we are currently developing more powerful behavioral, EEG, and molecular methods, combined with computational neuroscience/network modeling tools, to further increase the WAR strain's contributions to contemporary neuroscience in addition to increasing knowledge in a wide array of neuropsychiatric and other comorbidities, given shared neural networks. During the many years that the WAR strain has been studied, a constantly expanding network of multidisciplinary collaborators has generated a growing research and knowledge network. Our current and major wish is to make the WARs available internationally to share our knowledge and to facilitate the planning and execution of multi-institutional projects, eagerly needed to contribute to paradigm shifts in epileptology. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".

Remote effects of short-term neonatal hyperthermia in Krushinsky-Molodkina rats prone to audiogenic seizures strain.

Using the audiogenic seizure prone Krushinsky-Molodkina rat strain, it was demonstrated that short-term (5 min) exposure of 14-day-old pups to an elevated temperature (42°C) resulted in a significant decrease in audiogenic seizure severity at the age of 1 month. Presumably, this effect is determined by the activation of the heat-shock protein system (stress proteins).

Audiogenic kindling and secondary subcortico-cortical epileptogenesis: Behavioral correlates and electrographic features.

Human epilepsy is usually considered to result from cortical pathology, but animal studies show that the cortex may be secondarily involved in epileptogenesis, and cortical seizures may be triggered by extracortical mechanisms. In the audiogenic kindling model, recurrent subcortical (brainstem-driven) seizures induce secondary epileptic activation of the cortex. The present review focuses on behavioral and electrographic features of the subcortico-cortical epileptogenesis: (1) behavioral expressions of traditional and mild paradigms of audiogenic kindling produced by full-blown (generalized) and minimal (focal) audiogenic seizures, respectively; (2) electrographic manifestations of secondary epileptic activation of the cortex - cortical epileptic discharge and cortical spreading depression; and (3) persistent individual asymmetry of minimal audiogenic seizures and secondary cortical events produced by their repetition. The characteristics of audiogenic kindling suggest that this model represents a unique experimental approach to studying cortical epileptogenesis and network aspects of epilepsy. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".

Startle Response in Progressive Myoclonic Epilepsy.

Cortical reflex myoclonus is a typical feature of progressive myoclonic epilepsy (PME) in which it is accompanied by other types of mostly drug-resistant seizures and progressive neurological signs. Although PME is characterized by cortical hyperexcitability, studies have demonstrated atrophy and degenerative changes in the brainstem in various types of PME. Thus, we have questioned whether any stimuli may trigger a hyperactive response of brainstem reticular formation in PME and investigated the startle reflex in individuals with PME. We recorded the auditory startle response (ASR) and the startle response to somatosensory inputs (SSS) in patients with PME, and compared the results with healthy volunteers and patients with other types of drug-resistant epilepsy. All patients were using antiepileptic drugs (AEDs), 12 were on multiple AEDs. The probability of ASR was significantly lower and mean onset latency was longer in patients with PME compared with other groups. SSS responses over all muscles were low in both the PME and drug-resistant epilepsy groups; however, the differences were not statistically significant. The presence of a response over the biceps brachii muscle was zero in the PME group and showed a borderline difference compared with the other groups. Decreased probability and prolonged latencies of ASR in PME indicate inhibition of reflex circuit. A trend for decreased responses of SSS suggests hypoactive SSS in both PME and other epilepsy groups. Hypoactive ASR in PME and hypoactive SSS in both PME and other epilepsies may be attributed to the degeneration of pontine reticular nuclei in PME and functional inhibition by AEDs in both disorders.

Musicogenic Epilepsy and Treatment of Affective Disorders: Case Report and Review of Pathogenesis.

Musicogenic epilepsy is a rare syndrome in which music triggers seizures. Affective network processing appears to play a key role in epileptogenesis. Many people with epilepsy suffer from comorbid affective disorders, the shared basis of which involves similar pathophysiologies, including deficiencies of serotonergic and noradrenergic function. Seizures and mood disorders may thus have reciprocal effects on one another, particularly in emotionally precipitated syndromes such as musicogenic epilepsy. I report a man with long-standing depression and anxiety who developed focal epilepsy that evolved into musicogenic seizures. His case suggests a pathophysiologic basis for this shared phenomenon.

Ictal electrographic pattern of focal subcortical seizures induced by sound in rats.

It is now recognized that both generalized and focal seizures may originate in subcortical structures. The well-known types of focal subcortically-driven seizures are gelastic seizures in patients with the hypothalamic hamartoma and sound-induced seizures in rodents with audiogenic epilepsy. The seizures are generated by subcortical intrinsically epileptogenic focus, the hamartoma in humans and the inferior colliculus (IC) in rodents. In patients with gelastic epilepsy additional seizure types may develop with time that are supposed to result from secondary epileptogenesis and spreading of epileptic discharges to the cortex. Repeated audiogenic seizures can also lead to development of additional seizure behavior and secondary epileptic activation of the cortex. This process, named audiogenic kindling, may be useful for studying secondary subcortico-cortical epileptogenesis. Using intracollicular and intracortical recordings, we studied an ictal electrographic pattern of focal subcortical seizures induced by repeated sound stimulation in Wistar audiogenic-susceptible rats. The audiogenic seizures, representing brief attacks of paroxysmal unidirectional running, were accompanied by epileptiform abnormalities in the IC, mostly on the side ipsilateral to run direction, and enhanced rhythmic 8-9Hz activity in the cortex. With repetition of the subcortical seizures and kindling development, a secondary cortical discharge began to follow the IC seizure. The secondary discharge initially involved the cortex homolateral to the side of dominant subcortical epileptiform abnormalities and behaviorally expressed as limbic (partial) clonus. Kindling progression was associated with bilateralization of the secondary cortical discharge, an increase in its amplitude and duration, intensification of associated behavioral seizures (from partial clonus to generalized tonic-clonic convulsions). Thus, ictal recordings during brief audiogenic running seizures showed their focal subcortical origin. Repetition of the subcortical seizures may result in secondary subcortico-cortical epileptogenesis manifested by emergence and progressive intensification of epileptiform discharges in the cortex.

Musicogenic epilepsy.

Musicogenic epilepsy, which is a form of reflex epilepsy, is characterized by the triggering of epileptic seizures by specific music experiences. Individuals with musicogenic epilepsy differ in the music trigger, but may have similar seizures. Typically, these seizures are focal dyscognitive and have a temporal-lobe origin with a limbic system distribution. As such, the music trigger is likely related to either an emotional or memory aspect of music perception. Investigations into musicogenic epilepsy may lead to a better understanding of seizure propagation within the brain and of neurologic aspects of the music experience. Successful treatment of medication-resistant musicogenic epilepsy has been achieved with anterior temporal-lobe resection.

Comparative potency of sensory-induced brainstem activation to trigger spreading depression and seizures in the cortex of awake rats: Implications for the pathophysiology of migraine aura.

BACKGROUND: Migraine and epilepsy are highly co-morbid neurological disorders associated with episodic dysfunction of both cortical and subcortical networks. The study examined the interrelation between cortical spreading depression, the electrophysiological correlate of migraine aura and seizures triggered at cortical and brainstem levels by repeated sound stimulation in rats with acoustic hypersensitivity (reflex audiogenic epilepsy). METHOD: In awake, freely moving rats with innate audiogenic epilepsy, 25 episodes of running seizure (brainstem seizures) were induced by repeated sound stimulation. Spreading depression and seizures were recorded using implanted cortical electrodes. RESULTS: The first sound-induced brainstem seizures evoked neither spreading depression nor seizures in the cortex. With repetition, brainstem seizures began to be followed by a single cortical spreading depression wave and an epileptiform discharge. Spreading depression was more frequent an early cortical event than seizures: spreading depression appeared after 8.4 ± 1.0 repeated stimulations in 100% rats (n = 24) while cortical seizures were recorded after 12.9 ± 1.2 tests in 46% rats. Brainstem seizure triggered unilateral long-latency spreading depression. Bilateral short-latency cortical spreading depression was recorded only after intense cortical seizures. CONCLUSION: These data show that episodic brainstem activation is a potent trigger of unilateral cortical spreading depression. Development of intense seizures in the cortex leads to initiation of spreading depression in multiple cortical sites of both hemispheres.

The visual system in eyelid myoclonia with absences.

OBJECTIVE: To investigate the functional and structural brain correlates of eyelid myoclonus and absence seizures triggered by eye closure (eye closure sensitivity [ECS]). METHODS: Fifteen patients with eyelid myoclonus with absences (EMA, Jeavons syndrome), 14 patients with idiopathic generalized epilepsies (IGE) without ECS, and 16 healthy controls (HC) underwent an electroencephalography (EEG)-correlated functional magnetic resonance imaging (fMRI) and voxel brain morphometry (VBM) protocol. The functional study consisted of 30-second epochs of eyes-open and eyes-closed conditions. The following EEG events were marked and the relative fMRI maps obtained: (1) eye closure times, (2) spontaneous blinking, and (3) spontaneous and eye closure-triggered spike and wave discharges (SWD; for EMA and IGE). Within-group and between-groups comparisons were performed for fMRI and VBM data as appropriate. RESULTS: In EMA compared to HC and IGE we found: (1) higher blood oxygenation level-dependent (BOLD) signal related to the eye closure over the visual cortex, the posterior thalamus, and the network implicated in the motor control of eye closure, saccades, and eye pursuit movements; and (2) increments in the gray matter concentration at the visual cortex and thalamic pulvinar, whereas decrements were observed at the bilateral frontal eye field area. No BOLD differences were detected when comparing SWD in EMA and IGE. INTERPRETATION: Results demonstrated altered anatomo-functional properties of the visual system in EMA. These abnormalities involve a circuit encompassing the occipital cortex and the cortical/subcortical systems physiologically involved in the motor control of eye closure and eye movements. Our work supports EMA as an epileptic condition with distinctive features and provides a contribution to its classification among epileptic syndromes.

Loudness perception affected by early age hearing loss.

Tinnitus and hyperacusis, commonly seen in adults, are also reported in children. Although clinical studies found children with tinnitus and hyperacusis often suffered from recurrent otitis media, there is no direct study on how temporary hearing loss in the early age affects the sound loudness perception. In this study, sound loudness changes in rats affected by perforation of the tympanic membranes (TM) have been studied using an operant conditioning based behavioral task. We detected significant increases of sound loudness and susceptibility to audiogenic seizures (AGS) in rats with bilateral TM damage at postnatal 16 days. As increase to sound sensitivity is commonly seen in hyperacusis and tinnitus patients, these results suggest that early age hearing loss is a high risk factor to induce tinnitus and hyperacusis in children. In the TM damaged rats, we also detected a reduced expression of GABA receptor δ and α6 subunits in the inferior colliculus (IC) compared to the controls. Treatment of vigabatrin (60 mg/kg/day, 7-14 days), an anti-seizure drug that inhibits the catabolism of GABA, not only blocked AGS, but also significantly attenuated the loudness response. Administration of vigabatrin following the early age TM damage could even prevent rats from developing AGS. These results suggest that TM damage at an early age may cause a permanent reduction of GABA tonic inhibition which is critical towards the maintenance of normal loudness processing of the IC. Increasing GABA concentration during the critical period may alleviate the impairment in the brain induced by early age hearing loss.

Cardiac dysfunction in rats prone to audiogenic epileptic seizures.

PURPOSE: Cardiac dysfunction is one of the possible causes of sudden unexpected death in epilepsy (SUDEP). Therefore, the objective of this study was to evaluate cardiac and electrocardiographic parameters in rats with audiogenic epileptic seizures (WAR--Wistar audiogenic rats). METHODS: In vivo arterial pressure, heart rate (HR), autonomic tone and electrocardiography (ECG) were measured in awake animals in order to examine cardiac function and rhythm. Ex vivo, the Langendorff technique was used to analyze the cardiac function and the severity of reperfusion arrhythmias. In vitro, confocal microscopy was used to evaluate calcium transient parameters of isolated ventricular cardiomyocytes. RESULTS: In vivo autonomic tone evaluation revealed enhanced sympathetic activity, changes in cardiac function with increased systolic arterial pressure and higher basal HR in WAR. In addition, ECG analysis demonstrated electrical alterations with prolongation of the QT interval and QRS complex in these animals. Ex vivo, we observed a decrease in systolic tone and HR and an increase in the duration of ischemia/reperfusion arrhythmias in WAR. Moreover, intracellular Ca2+ handling analysis revealed an increase in the peak of calcium and calcium transient decay in audiogenic rats. Treatment with atenolol (ß1-adrenergic antagonist) normalized the systolic tone, reduced cardiac hypertrophy and the associated increase in the susceptibility to reperfusion arrhythmias observed in WAR. CONCLUSION: We present evidence that chronic disturbances in sympathetic tone in WAR cause increases the risk to life-threatening arrhythmias. Our results support a relationship between seizures, cardiac dysfunction and cardiac arrhythmias, which may contribute to the occurrence of SUDEP.

Reflex myoclonic epilepsy in infancy: a multicenter clinical study.

PURPOSE: To describe the clinical and electroencephalographic (EEG) features of reflex myoclonic epilepsy in infancy (RMEI) and long-term cognitive outcome. METHODS: We enrolled 31 children from 16 neuropediatric centres in Italy, who underwent clinical and video-EEG evaluation. Cognitive assessment was performed in all patients using standardized psychometric tests. RESULTS: The age at onset ranged from 3 to 24 months of age. Seizures were characterised in all patients by symmetric myoclonic seizures (MS), triggered by sudden unexpected acoustic (38.7%) or tactile stimuli (29%) or both (29%). Spontaneous attacks were reported in 32.2% of the cases. Ictal EEG showed generalized high-amplitude 3 Hz polyspike and wave discharges, synchronous with brief rhythmic bursts of electromyographic activity. Patients were re-evaluated after a period of 7.2 ± 5.6 years. The prognosis for seizure control was excellent in all cases and reflex MS disappeared spontaneously or after valproate treatment. The cognitive outcome was excellent in 90.3% of children. CONCLUSIONS: RMEI appears to be a variety of idiopathic generalized epilepsy with specific features that occurs in developmentally normal children.

Networks involved in seizure initiation. A reading epilepsy case studied with EEG-fMRI and MEG.

OBJECTIVE: To define the ictal cortical/subcortical network of reading-induced seizures. METHODS: We analyzed ictal magnetoencephalography (MEG) and EEG-correlated fMRI (EEG-fMRI) data in a unique patient with reading epilepsy (RE) affected by frequent perioral reflex myocloni triggered by reading silently. RESULTS: Ictal MEG corroborated EEG localization and revealed activity extending precentrally into Brodmann area (BA) 6. fMRI blood oxygen level-dependent (BOLD) signal changes in the left deep piriform cortex (PFC) and left BA6 preceded seizures and occurred before BOLD changes were observed in thalamus and right inferior frontal gyrus (BA44). Dynamic causal modeling provided evidence of a causal link between hemodynamic changes in the left PFC and reading-evoked seizures. CONCLUSION: Our findings support the important role of deep cortical and subcortical structures, in particular the frontal PFC, as key regions in initiating and modulating seizure activity. In our patient with RE, BA6 appeared to be the area linking cognitive activation and seizure activity.

[Effects of ionotropic glutamate receptor channel blockers on the development of audiogenic seizures in Krushinski-Molodkina rats].

The action of noncompetitive blockers of glutamate receptors has been investigated on Krushinski-Molodkina rats genetically-prone to audiogenic seizures. The selective blockers of NMDA receptor channels, memantine and IEM-1921, and their dicationic homologues, IEM-1925 and IEM-1754, capable of blocking in varying degrees both NMDA and Ca-permeable AMPA receptor channels, were studied. The drugs were injected intramuscularly to rats with the different time intervals (30 min, 1, 2 or 3 hours) before sound signal. The effects of the drugs on latent period of initial locomotor activity provoked by audio stimulation (8 kHz sine-wave tone, 90 dB volume), the appearance of clonic convulsions of different intensities, and, finally, tonic convulsions with limb and tail extension were evaluated. Within 30 min after injection IEM-1921 at a dose of 5 mg/kg, 33% of rats manifested a complete absence of convulsive reactions to sound, and in 59% of rats audiogenic seizures occured only in the form of motor excitation without a generalized clonic-tonic convulsions. Memantine at a dose of 5 mg/kg did not cause a complete blockade of seizures, but after 1 h of injection in 50% of the rats and after 2 h in 70% of rats a weakening of the audiogenic seizures to the level of motor excitation only was observed. After 3 hrs after administration of blockers its anticonvulsive action weakened significantly (p < 0.01). Dicationic blockers that block both NMDA and AMPA/kainate receptors, IEM-1925 (in doses of 0.001-20.0 mg/kg) and IEM-1754 (0.025-50.0 mg/kg), did not affect audiogenic clonic-tonic convulsive reactions. The involvement of activation of NMDA and calcium permeable AMPA/kainate receptors in the pathogenesis of audiogenic seizures is discussed.