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Summary: Objective: Fibroblast growth factor homologous factors (FHFs) are brain and cardiac sodium channel‐binding proteins that modulate channel density and inactivation gating. A recurrent de novo gain‐of‐function missense mutation in the FHF1(FGF12) gene (p.Arg52His) is associated with early infantile epileptic encephalopathy 47 (EIEE47; Online Mendelian Inheritance in Man database 617166). To determine whether the FHF1 missense mutation is sufficient to cause EIEE and to establish an animal model for EIEE47, we sought to engineer this mutation into mice. Methods: The Arg52His mutation was introduced into fertilized eggs by CRISPR (clustered regularly interspaced short palindromic repeats) editing to generate Fhf1R52H/F+ mice. Spontaneous epileptiform events in Fhf1R52H/+ mice were assessed by cortical electroencephalography (EEG) and video monitoring. Basal heart rhythm and seizure‐induced arrhythmia were recorded by electrocardiography. Modulation of cardiac sodium channel inactivation by FHF1BR52H protein was assayed by voltage‐clamp recordings of FHF‐deficient mouse cardiomyocytes infected with adenoviruses expressing wild‐type FHF1B or FHF1BR52H protein. Results: All Fhf1R52H/+ mice experienced seizure or seizurelike episodes with lethal ending between 12 and 26 days of age. EEG recordings in 19–20‐day‐old mice confirmed sudden unexpected death in epilepsy (SUDEP) as severe tonic seizures immediately preceding loss of brain activity and death. Within 2–53 s after lethal seizure onset, heart rate abruptly declined from 572 ± 16 bpm to 108 ± 15 bpm, suggesting a parasympathetic surge accompanying seizures that may have contributed to SUDEP. Although ectopic overexpression of FHF1BR52H in cardiomyocytes induced a 15‐mV depolarizing shift in voltage of steady‐state sodium channel inactivation and slowed the rate of channel inactivation, heart rhythm was normal in Fhf1R52H/+ mice prior to seizure. Significance: The Fhf1 missense mutation p.Arg52His induces epileptic encephalopathy with full penetrance in mice. Both Fhf1 (p.Arg52His) and Scn8a (p.Asn1768Asp) missense mutations enhance sodium channel Nav1.6 currents and induce SUDEP with bradycardia in mice, suggesting an FHF1/Nav1.6 functional axis underlying altered brain sodium channel gating in epileptic encephalopathy. [ABSTRACT FROM AUTHOR]

Objective: BRD2 is a human gene repeatedly linked to and associated with juvenile myoclonic epilepsy (JME). Here, we define the developmental stage when increased seizure susceptibility first manifests in heterozygous Brd2+/‐ mice, an animal model of JME. We wanted to determine (1) whether seizure susceptibility correlates with the proven decrease of γ‐aminobutyric acidergic (GABAergic) neuron numbers and (2) whether the seizure phenotype can be affected by sex hormones. Methods: Heterozygous (Brd2+/‐) and wild‐type (wt) mice of both sexes were tested for flurothyl‐induced seizure susceptibility at postnatal day 15 (P15; wt, n = 13; Brd2+/‐, n = 20), at P30 (wt, n = 20; Brd2+/‐, n = 20), and in adulthood (5‐6 months of age; wt, n = 10; Brd2+/‐, n = 12). We measured latency to clonic and tonic‐clonic seizure onset (flurothyl threshold). We also compared relative density of parvalbumin‐positive (PVA+) and GAD67+ GABA neurons in the striatum and primary motor (M1) neocortex of P15 (n = 6‐13 mice per subgroup) and P30 (n = 7‐10 mice per subgroup) mice. Additional neonatal Brd2+/‐ mice were injected with testosterone propionate (females) or formestane (males) and challenged with flurothyl at P30. Results: P15 Brd2+/‐ mice showed no difference in seizure susceptibility compared to P15 wt mice. However, even at this early age, Brd2+/‐ mice showed fewer PVA+ neurons in the striatum and M1 neocortex. Compared to wt, the striatum in Brd2+/‐ mice showed an increased proportion of immature PVA+ neurons, with smaller cell bodies and limited dendritic arborization. P30 Brd2+/− mice displayed increased susceptibility to flurothyl‐induced clonic seizures compared to wt. Both genotype and sex strongly influenced the density of PVA+ neurons in the striatum. Susceptibility to clonic seizures remained increased in adult Brd2+/‐ mice, and additionally there was increased susceptibility to tonic‐clonic seizures. In P30 females, neonatal testosterone reduced the number of flurothyl‐induced clonic seizures. Significance: A decrease in striatal PVA+ GABAergic neurons developmentally precedes the onset of increased seizure susceptibility and likely contributes to the expression of the syndrome. [ABSTRACT FROM AUTHOR]

Incidences of pesticide poisonings are a significant cause of morbidity and mortality worldwide. The seizure-inducing rodenticide tetramethylenedisulfotetramine is one of the most toxic of these agents. Although banned, it has been responsible for thousands of accidental, intentional, and mass poisonings in mainland China and elsewhere. An optimal regimen for treatment of poisoning has not been established. Its facile synthesis from easily obtained starting materials, extreme potency, and lack of odor, color, or taste make it a potential chemical threat agent. This review describes the toxicologic properties of this agent, more recent advances in our understanding of its properties, and recommendations for future research. [ABSTRACT FROM AUTHOR]

Objective This study attempted to validate the effects of neonatal estradiol in ameliorating the spasms in the prenatally betamethasone-primed N-methyl- d-aspartate ( NMDA) model of infantile spasms in rats as shown previously in a mouse Arx gene knock-in expansion model of infantile spasms. Methods Neonatal rats prenatally exposed to betamethasone (on day 15 of pregnancy) were treated with subcutaneous 40 ng/g estradiol benzoate ( EB) between postnatal days (P)3-P10 or P0-P5. A synthetic estrogen analogue, diethylstilbestrol, was used between P0 and P5 (2 μg per rat, s.c.). On P12, P13, and P15, the rats were subjected to NMDA-triggered spasms, and latency to onset and number of spasms were evaluated. Rats with EB on P3-P10 were tested after spasms in the open field, novel object recognition, and elevated plus maze to determine effects of treatment on behavior. Additional rats with P3-P10 or P0-P5 EB were investigated for γ-aminobutyric acid ( GABA)ergic neurons (glutamate decarboxylase [ GAD]67 expression) in the neocortex. As a positive control, a group of rats received either subcutaneous adrenocorticotropic hormone ( ACTH) (2 × 0.3 mg/kg on P12 and 3 × 0.3 mg/kg on P13 and P14) or vehicle after the first episode of spasms on P12. Results Neither EB treatment nor diethylstilbestrol consistently affected expression of spasms in this model, although we found a significant increase in GAD67-immunopositive cells in the neocortex after P3-P10 and P0-P5 EB treatment, consistent with a study in mice. Behavioral tests showed increase in lateralization in male rats treated with P3-P10 EB, a behavioral trait usually associated with female sex. Diethylstilbestrol treatment in male rats resulted in arrested pubertal descent of testes. ACTH had robust effects in suppressing spasms. Significance Treatment of infantile spasms ( IS) using neonatal EB may be justified in those cases of IS that present with detectable deficits in GABAergic neurons. In other types of IS, the efficacy of neonatal EB and its analogues is not supported. [ABSTRACT FROM AUTHOR]

Purpose: Rapamycin (RAP) has certain antiepileptogenic features. However, it is unclear whether these effects can be explained by the anticonvulsant action of RAP, which has not been studied. To address this question, we tested potential anticonvulsant effects of RAP in immature and adult rats using different seizure models and treatment paradigms. In addition, we studied changes in the expression of neuropeptide Y (NPY) induced by RAP, which may serve as an indirect target of the RAP action. Methods: A complex approach was adopted to evaluate the anticonvulsant potential of RAP: We used flurothyl-, pentylenetetrazole (PTZ)-, N-methyl- d-aspartate (NMDA)-, and kainic acid (KA)-induced seizures to test the effects of RAP using different pretreatment protocols in immature and adult rats. We also evaluated expression of NPY within the primary motor cortex, hippocampal CA1, and dentate gyrus (DG) after different pretreatments with RAP in immature rats. Key Findings: We found the following: (1) RAP administered with short-term pretreatment paradigms has a weak anticonvulsant potential in the seizure models with compromised inhibition. (2) Lack of RAP efficacy correlates with decreased NPY expression in the cortex, CA1, and DG. Specifically in immature rats, a single dose of RAP (3 mg/kg) 4 or 24 h before seizure testing had anticonvulsant effects against PTZ-induced seizures. In the flurothyl seizure model only the 4-h pretreatment with RAP was anticonvulsant in the both age groups. Short-term pretreatments with RAP had no effects against NMDA- and KA-induced seizures tested in immature rats. Long-term pretreatments with RAP over 8 days did not show beneficial effect in all tested seizure models in developing rats. Moreover, the long-term pretreatment with RAP had a slight proconvulsant effect on KA-induced seizures. In immature rats, any lack of anticonvulsant effect (including proconvulsant effect of multiple doses of RAP) was associated with downregulation of NPY expression in the cortex and DG. In immature animals, after a single dose of RAP with 24 h delay, we found a decrease of NPY expression in DG, and CA1 as well. Significance: Our data show weak age-, treatment paradigm-, and model-specific anticonvulsant effects of RAP as well as loss of those effects after long-term RAP pretreatment associated with downregulation of NPY expression. These findings suggest that RAP is a poor anticonvulsant and may have beneficial effects only against epileptogenesis. In addition, our data present new insights into mechanisms of RAP action on seizures indicating a possible connection between mammalian target of rapamycin (mTOR) signaling and NPY system. [ABSTRACT FROM AUTHOR]

The antiepileptic drugs (AEDs) introduced during the past two decades have provided several benefits: they offered new treatment options for symptomatic treatment of seizures, improved ease of use and tolerability, and lowered risk for hypersensitivity reactions and detrimental drug-drug interactions. These drugs, however, neither attenuated the problem of drug-refractory epilepsy nor proved capable of preventing or curing the disease. Therefore, new preclinical screening strategies are needed to identify AEDs that target these unmet medical needs. New therapies may derive from novel targets identified on the basis of existing hypotheses for drug-refractory epilepsy and the biology of epileptogenesis; from research on genetics, transcriptomics, and epigenetics; and from mechanisms relevant for other therapy areas. Novel targets should be explored using new preclinical screening strategies, and new technologies should be used to develop medium- to high-throughput screening models. In vivo testing of novel drugs should be performed in models mimicking relevant aspects of drug refractory epilepsy and/or epileptogenesis. To minimize the high attrition rate associated with drug development, which arises mainly from a failure to demonstrate sufficient clinical efficacy of new treatments, it is important to define integrated strategies for preclinical screening and experimental trial design. An important tool will be the discovery and implementation of relevant biomarkers that will facilitate a continuum of proof-of-concept approaches during early clinical testing to rapidly confirm or reject preclinical findings, and thereby lower the risk of the overall development effort. In this review, we overview some of the issues related to these topics and provide examples of new approaches that we hope will be more successful than those used in the past. [ABSTRACT FROM AUTHOR]

Summary We have developed a new model of cryptogenic infantile spasms with prenatal betamethasone brain priming to increase susceptibility to development-specific spasms triggered by N-methyl- d-aspartate (NMDA). A recent clinical study linked severe prenatal stress to increased risk for development of infantile spasms. Here, we determined whether prenatal restraint stress (2 × 45 min) in rats on gestational day 15 would increase susceptibility to develop spasms on postnatal day 15. Prenatal stress significantly accelerated onset and increased number of NMDA-triggered spasms compared to handled controls. A single adrenocorticotropic hormone (ACTH or corticotropin) dose delivered acutely had no effects, whereas long-term (3 day) ACTH pretreatment significantly increased latency to onset and decreased number of spasms (an effect similar to that in the human condition). Our data support the notion that extra care should be provided during pregnancy to minimize stress. [ABSTRACT FROM AUTHOR]

Summary Purpose: To determine whether a new model of cryptogenic infantile spasms consisting of prenatal priming with betamethasone and postnatal trigger of spasms by N-methyl- d-aspartate (NMDA) responds to chronic adrenocorticotropic hormone (ACTH) treatment, and has electroencephalography (EEG) signature, efficacy of treatments, and behavioral impairments similar to those in human infantile spasms. Methods: Rats prenatally primed with betamethasone on gestational day 15 were used. Spasms were triggered with NMDA between postnatal days (P) 10 and 15 in a single session or in multiple sessions in one subject. The expression of spasms was compared to prenatally saline-injected controls. Effects of relevant treatments (ACTH, vigabatrin, methylprednisolone, rapamycin) were determined in betamethasone-primed rats. In the rats after spasms, behavioral evaluation was performed in the open field and elevated plus maze on P20-22. Key Findings: NMDA at P10-15 (the rat 'infant' period) triggers the spasms significantly earlier and in greater numbers in the prenatal betamethasone-exposed brain compared to controls. Similar to human condition, the spasms occur in clusters. Repeated trigger of spasms is associated with ictal EEG electrodecrements and interictal large-amplitude waves, a possible rat variant of hypsarrhythmia. Chronic ACTH treatment in a randomized experiment, and chronic pretreatment with methylprednisolone significantly suppress the number of spasms similar to the human condition. Pretreatment with vigabatrin, but not rapamycin, suppressed the spasms. Significant behavioral changes occurred following multiple bouts of spasms. Significance: The model of infantile spasms has remarkable similarities with the human condition in semiology, EEG, pharmacologic response, and long-term outcome. Therefore, the model can be used to search for novel and more effective treatments for infantile spasms. [ABSTRACT FROM AUTHOR]

Infantile spasms (IS) is a devastating epilepsy syndrome of childhood. IS occurs in 3–12-month-old infants and is characterized by spasms, interictal electroencephalography (EEG) hypsarrhythmia, and profound mental retardation. Hormonal therapy [adrenocorticotropic hormone (ACTH), corticosteroids] is frequently used, but its efficacy is tainted by severe side effects. For research of novel therapies, a validated animal model of IS is required. We propose the model of spastic seizures triggered by N-methyl-d-aspartate (NMDA) in infant rats prenatally exposed to betamethasone. The spasms have remarkable similarity to human IS, including motor flexion spasms, ictal EEG electrodecrement, and responsiveness to ACTH. Interestingly, the spasms do not involve the hippocampus. Autoradiographic metabolic mapping as well as tagging of the areas of neuronal excitation with c-fos indicates a strong involvement of hypothalamic structures such as the arcuate nucleus, which has significant bilateral connections with other hypothalamic nuclei as well as with the brainstem. [ABSTRACT FROM AUTHOR]

Estrogens are essential for normal brain functions. The effects of estrogens on seizures are contradictory. More studies are necessary to determine under which conditions the estrogens have proconvulsant effects and when the estrogens may have beneficial action in patients with epilepsy. [ABSTRACT FROM AUTHOR]

Studies of the effects of prenatal exposure (to drugs or environmental factors) on postnatal brain morphology and function have an important role in assessing adverse effects of prenatal administration of corticosteroids in obstetrics, in studying the impairment of the offspring due to maternal drug abuse, as well as in studies of the influence of other environmental factors (such as toxins or stress). Timing, duration, and dose of the prenatal exposure play a significant role in the postnatal expression of the impact. However, data interpretation may be complicated by additional factors. As mixed litters of prenatally exposed subjects are evaluated, significant differences between males and females may occur. Additionally in females, cyclical changes in ovarian steroids may interfere with the effects of prenatal impact. Developmental differences may be also present, and data from infant, juvenile, prepubertal, and adult individuals cannot be simply compared. Finally, prenatal treatment is a stressful event and may present itself as prenatal stress, misguiding the interpretation. Postnatal environmental factors in raising the offspring, such as housing, maternal care, light–dark cycle, and weaning age can also change the data in such a way, which makes comparisons between different research laboratories impossible. [ABSTRACT FROM AUTHOR]

In vivo, severe hypoglycemia is frequently associated with seizures. The hippocampus is a structure prone to develop seizures and seizure-induced damage. Patients with repeated hypoglycemic episodes have frequent memory problems, suggesting impaired hippocampal function. Here we studied the effects of moderate hypoglycemia on primarily generalized flurothyl-induced seizures in vivo and, using EEG recordings, we determined involvement of the hippocampus in hypoglycemic seizures. Moderate systemic hypoglycemia had proconvulsant effects on flurothyl-induced clonic (forebrain) seizures. During hypoglycemic seizures, seizure discharges were recorded in the hippocampus. Thus, we continued the studies in combined entorhinal cortex–hippocampus slices in vitro. However, in vitro, decreases in extracellular glucose from baseline 10 mm to 2 or 1 mm did not induce any epileptiform discharges. In fact, low glucose (2 and 1 mm) attenuated preexisting low-Mg2+-induced epileptiform activity in the entorhinal cortex and hippocampal CA1 region. Osmolarity compensation in low-glucose solution using mannitol impaired slice recovery. Additionally, using paired-pulse stimuli we determined that there was no impairment of GABAA inhibition in the dentate gyrus during glucopenia. The data strongly indicate that, although forebrain susceptibility to seizures is increased during moderate in vivo hypoglycemia and the hippocampus is involved during hypoglycemic seizures, glucose depletion in vitro contributes to an arrest of epileptiform activity in the system of the entorhinal cortex–hippocampus network and there is no impairment of net GABAA inhibition during glucopenia. [ABSTRACT FROM AUTHOR]

Abstract: In brain slices from prenatally saline-exposed female rats during proestrus and diestrus, long-term potentiation (LTP) can be induced in the lateral perforant pathway (LPP). Prenatal morphine exposure suppresses LTP induction in the LPP during proestrus. Here we studied synaptic plasticity in the LPP in slices from female rats prenatally exposed to morphine. Two additional factors were investigated: the role of the estrous cycle and role of glucocorticoid receptors. Hippocampal slices were prepared from adult, prenatally saline- or morphine-exposed female rats. One hour prior to decapitation, vaginal smears were obtained and the rats either in proestrus or diestrus were treated with a non-specific glucocorticoid receptor antagonist mifepristone (RU486) or with a vehicle. LPP was stimulated with high-frequency stimulation. Short-tem plasticity (STP) and the induction and maintenance of long-term potentiation (LTP) were assessed. In all groups of prenatally saline-exposed rats, LTP was induced and maintained with the exception of RU486-treated rats during proestrus where the LTP was induced but not maintained. In prenatally morphine-exposed females in diestrus, both STP and LTP were induced after postnatal vehicle treatment. In morphine-exposed, proestrous females, neither STP nor LTP were induced irrespective of the postnatal treatment. Thus, prenatal morphine exposure suppresses the induction of LTP in the LPP, except during diestrus. Data indicate that the induction and maintenance of LTP in the LPP in hippocampal slices from female rats is multifactorial: ovarian steroids and functionality of glucocorticoid receptors cooperation are necessary for induction and maintenance of the LTP, prenatal morphine exposure interferes with this process possibly by it''s long-term effects on synaptic plasticity. [Copyright &y& Elsevier]

Purpose:Development and sex hormones are important determinants of seizure susceptibility. Seizures develop in the immature brain more readily than in the mature brain. Male children experience a higher incidence of epilepsy or unprovoked seizures than do female children. Sex-specific differences in the development of seizure-suppressing neuronal networks may account, at least in part, for this increased age- and sex-related susceptibility to seizures. The control of seizures can be influenced by the substantia nigra pars reticulata (SNR) in an age- and sex-specific manner. In the adult male rat SNR, two topographically discrete regions (SNRanterior and SNRposterior) mediate distinct effects on seizures, by using divergent output networks in response to localized infusions ofγ-aminobutyric acid (GABA)A agents, such as muscimol. The GABAA-sensitive“anticonvulsant” region is located in the SNRanterior, whereas the GABAA-sensitive“proconvulsant region is in the SNRposterior. In immature postnatal day (PN)15–21 male rats, the SNR is not topographically segregated, and GABAAergic drug infusions produce similar effects when applied in the SNRanterior or SNRposterior. Only a GABAA-sensitive proconvulsant network is evident. By contrast, female SNR does not contain any region that mediates muscimol-related proconvulsant effects. As with the adult, immature female rats do not develop a proconvulsant SNR region at any age.Methods:We measured the effects of SNR muscimol infusions on seizures in male rats castrated at birth to better understand the effects of testosterone on the formation of age- and sex-specific features of the SNR.Results:Neonatal castration permanently alters the maturation of the muscimol-sensitive SNR effect on seizures. The SNR of neonatally castrated rats develops functionally like the“female” SNR. The“proconvulsant” SNR region does not develop in the absence of testosterone in the immediate postnatal period. The“male” type of SNR effects can be induced in neonatally castrated rats by restoration of testosterone levels or in female rats by artificially increasing testosterone levels. Dihydrotestosterone and estrogen, produced by the reduction and aromatization of testosterone, respectively, are the direct mediators of testosterone actions. At PN0, onlyβ estrogen receptors are equally expressed in the SNRs of males and females and may be responsible for testosterone-mediated effects in both sexes.Conclusions:The phenotype of SNR GABAergic neurons, as characterized by GABAA-receptor subunit composition, by muscimol-induced electrophysiologic responses, and by connectivity of output networks each may be altered by the presence of testosterone. Higher KCC2 messenger RNA (mRNA) expression in female PN15 SNR neurons compared with males may be responsible for sex-related differences in muscimol-induced electrophysiologic responses. In summary, a growing body of compelling evidence identifying sex-related differences in the SNR implicates postnatal testosterone as a critical factor in the development of pro- or anticonvulsant circuits. The recognition of sex- and age-related features in the SNR holds the promise that these findings can be translated into the development of specific and effective treatments for seizure disorders. [ABSTRACT FROM AUTHOR]

Summary: Purpose: Animal studies and anecdotal human case reports have indicated that the subthalamic nucleus (STN) may be a site of anticonvulsant action. Methods: We tested the hypothesis that continuous electrical stimulation of the STN inhibits seizures acutely. We determined the effects of three stimulation frequencies, 130 Hz, 260 Hz, and 800 Hz, on generalized clonic and tonic–clonic flurothyl seizures. Adult male rats were implanted with concentric bipolar stimulating electrodes in the STN bilaterally. After recovery, rats underwent flurothyl seizures to compare the effects of each stimulation frequency on seizure threshold. Rats were tested 4 times, twice in the stimulated condition, and twice in the unstimulated condition. The order of trials was random, except that stimulation trials alternated with control trials. Flurothyl seizure thresholds under each stimulation condition were compared with control values from the same animal. Results: Bilateral stimulation of the STN at 130 Hz produced a significant increase in the seizure threshold for clonic flurothyl seizures, whereas stimulation at 260 Hz did not appear to have any effect on seizures. STN stimulation at 800 Hz significantly lowered seizure threshold for tonic–clonic seizures. Conclusions: We conclude that electrical stimulation of the STN can be anticonvulsant, but the effects appear to depend on the stimulation frequency and the type of seizure. [ABSTRACT FROM AUTHOR]

Summary: Purpose: We used the paired-pulse inhibition paradigm to determine whether the cell loss in the hilus of the dentate gyrus of female rats after kainic acid (KA)-induced status epilepticus (SE) is associated with functional changes in the dentate gyrus. Additionally, we determined whether the lost function could be preserved by using estrogen neuroprotection. Methods: Female rats were ovariectomized and treated either with estrogen replacement (four doses of 2 μg of estradiol every 24 h: two doses before SE, two doses after) or oil. SE was induced by I.P. administration of KA (16 mg/kg) and terminated after 5 h with pentobarbital. After 2 days, hippocampal/dentate gyrus slices were prepared. Population spikes were recorded in the granule cell layer as a response to mixed perforant-path stimulation (10- to 1,000-ms interstimulus intervals). Ratios of the test response to conditioning response were evaluated. γ-Aminobutyric acid type B (GABAB ) receptors were blocked with 400 μ M CGP 35348. Results: In slices from oil-treated rats, SE induced a loss of paired-pulse inhibition in the dentate gyrus at the interstimulus intervals marking intermediate facilitation and late depression. There was no such loss of paired-pulse inhibition in estrogen-treated rats. CGP 35348 was unable to alter paired-pulse inhibition in slices form oil-treated rats. In slices from estrogen-treated rats, CGP decreased paired-pulse inhibition at 50–150-ms interstimulus intervals. Comparison of paired-pulse inhibition in slices from oil-treated rats with slices from estrogen-treated rats with CGP 35348 revealed a GABAB -independent difference at interstimulus intervals >300 ms. Conclusions: Our study demonstrated that there is a complete loss of GABAB receptor–mediated inhibition after KA-induced SE in the dentate gyrus. Pretreatment with estrogen can save GABA B -receptor function, probably by neuroprotection of... [ABSTRACT FROM AUTHOR]

Neurological complications of hypoglycemia often include seizures and fasting is a predisposing factor for seizures to occur. The mechanisms involved are unknown. In rats, insulin administration induces hypoglycemia, which may lead to generalized seizures with barrel rotations as a hallmark. Here we compared the incidence of barrel rotations in fasted and nonfasted rats. Further, we investigated the role of the substantia nigra pars reticulata (SNR) in control of barrel rotations using localized bilateral microinfusions of GABAA or GABAB receptor agonists (muscimol or baclofen, respectively) or an N-methyl-D-aspartate (NMDA) receptor antagonist (AP7). The incidence of barrel rotations was significantly higher in fasted compared to nonfasted rats. SNR infusions of muscimol were ineffective, while both baclofen and AP7 significantly decreased occurrence of barrel rotations. These data suggest that during hypoglycemia, the SNR seizure controlling system has different properties than in seizure models not involving a metabolic stress. [ABSTRACT FROM AUTHOR]