Gamma-aminobutyric Acid Antagonist Research Articles

Insights into the leveraging of GABAergic signaling in cancer therapy.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain of adult mammals. Several studies have demonstrated that the GABAergic system may regulate tumor development via GABA receptors, downstream cyclic adenosine monophosphate (cAMP) pathway, epithelial growth factor receptor (EGFR) pathway, AKT pathway, mitogen-activated protein kinase (MAPK) or extracellular signal-related kinases (ERK) pathway, and matrix metalloproteinase (MMP) pathway, although the exact mechanism is unclear. Pioneering studies reported that GABA signaling exists and functions in the cancer microenvironment and has an immunosuppressive effect that contributes to metastasis and colonization. This article reviews the molecular structures and biological functions of GABAergic components correlated with carcinogenesis, the mechanisms underlying GABAergic signaling that manipulate the proliferation and invasion of cancer cells, and the potential GABA receptor agonists and antagonists for cancer therapy. These molecules may provide an avenue for the development of specific pharmacological components to prevent the growth and metastasis of various cancers.

Brain tissue oxygen dynamics while mimicking the functional deficiency of interneurons.

The dynamic interaction between excitatory and inhibitory activity in the brain is known as excitatory-inhibitory balance (EIB). A significant shift in EIB toward excitation has been observed in numerous pathological states and diseases, such as autism or epilepsy, where interneurons may be dysfunctional. The consequences of this on neurovascular interactions remains to be elucidated. Specifically, it is not known if there is an elevated metabolic consumption of oxygen due to increased excitatory activity. To investigate this, we administered microinjections of picrotoxin, a gamma aminobutyric acid (GABA) antagonist, to the rabbit cortex in the awake state to mimic the functional deficiency of GABAergic interneurons. This caused an observable shift in EIB toward excitation without the induction of seizures. We used chronically implanted electrodes to measure both neuronal activity and brain tissue oxygen concentrations (PO2) simultaneously and in the same location. Using a high-frequency recording rate for PO2, we were able to detect two important phenomena, (1) the shift in EIB led to a change in the power spectra of PO2 fluctuations, such that higher frequencies (8-15 cycles per minute) were suppressed and (2) there were brief periods (dips with a duration of less than 100 ms associated with neuronal bursts) when PO2 dropped below 10 mmHg, which we defined as the threshold for hypoxia. The dips were followed by an overshoot, which indicates either a rapid vascular response or decrease in oxygen consumption. Our results point to the essential role of interneurons in brain tissue oxygen regulation in the resting state.

Functions of the GABAergic system on serum LH concentrations in pre-pubertal Nellore heifers

This study was conducted to evaluate the luteinizing hormone (LH) secretion pattern after gamma-aminobutyric acid (GABAA) antagonist to determine the effects of the GABAergic system on LH secretion during reproductive maturation in pre-pubertal Nellore heifers. Nellore heifers (n = 10) were administered a picrotoxin injection of 0.18 mg/kg, i.v. Blood samples were collected every 15 min for 3 h at different developmental stages (8, 10, 14 and 17 mo of age). Plasma concentrations of LH were quantified using an RIA (sensitivity of 0.04 ng/mL and CV of 15 %). There was an interaction between treatment and age (P = 0.034). Picrotoxin-treated heifers had lesser (P ≤ 0.05) LH mean concentrations during a 3 h period at 10 and 17 mo of age compared to control heifers (P ≤ 0.05). Comparing the period before and after Picrotoxin injection in the same animals, there was a 33 % decrease in LH concentration at 8 mo of age (P = 0.0165). These results indicate the GABAergic system has a stimulatory function in inducing LH secretion in pre-pubertal Nellore heifers. These findings corroborate previous results that GABA increases GnRH/LH secretion in other species during the pre-pubertal period.

Orexin in Dorsal Raphe Nucleus enhances Physical Activity and Energy Expenditure

Background Lateral hypothalamic (LH) orexin neurons modulate spontaneous physical activity (SPA), and energy expenditure (EE). Orexin deficiency results in weight gain, whereas heightened LH orexin sensitivity results in obesity resistance. Orexins act on multiple brain sites, including the serotonergic dorsal raphe nucleus (DRN), which receives excitatory projections from the orexin neurons. Our earlier studies show presence of both orexin-1 (OX1R) and orexin-2 receptors (OX2R) in DRN, and higher expression of OX1R and OX2R in DRN of obesity resistant (OR) rats. We hypothesized that orexin in DRN enhances SPA and EE. Secondarily, we hypothesized that DRN GABA (gamma-aminobutyric acid) signaling mediates the effect of orexin on SPA and EE. Methods We manipulated orexin tone in DRN either by direct injections of orexin A into DRN or by chemogenetic activation of LH orexin neurons in aged (~15 mo) orexin-cre mice. Mice were implanted with a guide cannula targeting DRN, and simultaneously prepared with the stimulatory (hM3Dq floxed) designer receptors exclusively activated by designer drugs (DREADD) virus in LH (N = 16). All mice recovered for 3 weeks to allow transfection of the DREADD virus, and randomly assigned to saline or clozapine N-oxide (CNO, DREADD activator) treatment. Mice were transferred to Promethion indirect calorimetry cages (Sable Systems International) to continuously monitor SPA and EE. Body weight and food intake were measured daily. After acclimation, mice received either IP vehicle or CNO (1 mg/kg) in a repeated measure design. Fifteen minutes prior to IP CNO or saline, animals were infused with either the GABA agonist muscimol (32.5 pmol/0.2 μl), GABA antagonist bicuculline (32.5 pmol/0.2 μl) or vehicle into DRN. In a separate experiment, either orexin A (250 pmol/0.2 μl) or saline was injected into DRN without IP CNO injection, to study the direct effect of DRN orexin on SPA and EE for 24h post-injection. Results We found that DREADD activation of LH orexin neurons increases SPA and EE. Manipulation of GABA receptors (by muscimol or bicuculline) in DRN did not affect orexin neuron activation induced enhancement of SPA. On the other hand, intra-DRN OXA enhanced SPA and EE in these mice up to 4h post-injection, without affecting food intake. Conclusions These results support the idea that OXA in DRN facilitates negative energy balance by increasing physical activity-induced energy expenditure. In addition, these data suggest that the DRN is a prominent site modulating OXA-stimulated SPA and EE, and that modulation of DRN OXA is a potential strategy to mitigate age-induced reductions in SPA and EE.

Catalpol and Mannitol, Two Components of Rehmannia glutinosa, Exhibit Anticonvulsant Effects Probably via GABAA Receptor Regulation.

Epilepsy is a brain disorder that affects millions of people worldwide and is usually managed using currently available antiepileptic drugs, which result in adverse effects and are ineffective in approximately 20–25% of patients. Thus, there is growing interest in the development of new antiepileptic drugs with fewer side effects. In a previous study, we showed that a Rehmannia glutinosa (RG) water extract has protective effects against electroshock- and pentylenetetrazol (PTZ)-induced seizures, with fewer side effects. In this study, the objective was to identify the RG components that are responsible for its anticonvulsant effects. Initially, a number of RG components (aucubin, acteoside, catalpol, and mannitol) were screened, and the anticonvulsant effects of different doses of catalpol, mannitol, and their combination on electroshock- and chemically (PTZ or strychnine)-induced seizures in mice, were further assessed. Gamma-aminobutyric acid (GABA) receptor binding assay and electroencephalography (EEG) analysis were conducted to identify the potential underlying drug mechanism. Additionally, treated mice were tested using open-field and rotarod tests. Catalpol, mannitol, and their combination increased threshold against electroshock-induced seizures, and decreased the percentage of seizure responses induced by PTZ, a GABA antagonist. GABA receptor binding assay results revealed that catalpol and mannitol are associated with GABA receptor activity, and EEG analysis provided evidence that catalpol and mannitol have anticonvulsant effects against PTZ-induced seizures. In summary, our results indicate that catalpol and mannitol have anticonvulsant properties, and may mediate the protective effects of RG against seizures.

薬剤誘発性吃逆の3症例：原因薬剤と機序(Three cases of drug–induced hiccup: causative drugs and mechanisms)

要旨 慢性・難治性吃逆には何らかの原因疾患があることが多いが，薬剤が原因となり得ることはあまり知られていない。筆者が経験した薬剤誘発性吃逆症例のうち3例を報告する。1例はステロイドが，1例は創感染治療に用いられたニューキノロン（NQ）系抗菌薬が，1例は抗腫瘍薬が原因と考えられた。吃逆中枢は延髄疑核近傍網様体内にあり，GABAによる抑制を受けている。そのためGABA拮抗作用をもつ薬剤は吃逆誘発作用をもつと考えられる。ステロイドはGABA促進作用と拮抗作用という相反する作用をもつことが報告されているが，吃逆中枢ではGABA拮抗作用が強いと考えられる。NQ系抗菌薬はGABA拮抗作用による痙攣誘発作用があり，吃逆誘発も同じ機序によると考えられる。抗腫瘍薬には痙攣誘発性のある薬剤があり，白質変性作用をもつことなどが示唆されGABA作用と関係する可能性が考えられる。薬剤誘発性吃逆は可能なら原因薬剤の中止・変更が望ましいが，不可能な場合はGABA–B作動薬であるバクロフェンの投与が有効な可能性がある。

Limitations of Local Brain Cooling on Generalized Motor Seizures from Unknown Foci in Awake Rats.

Local brain cooling of an epileptic focus at 15°C reduces the number of spikes on an electrocorticogram (ECoG), terminates seizures, and maintains neurological functions. In this study, we attempted to suppress generalized motor seizures (GMSs) by cooling a unilateral sensorimotor area. GMSs were induced in rats by intraperitoneal injection of bicuculline methiodide, an antagonist of gamma-aminobutyric acid. While monitoring the ECoG and behavior, the right sensorimotor cortex was cooled for 10 min using an implanted device. The number of spikes recorded from the cooled cortex significantly decreased to 71.2% and 62.5% compared with the control group at temperatures of 15 and 5°C (both P <0.01), respectively. The number of spikes recorded from the contralateral mirror cortex reduced to 61.7% and 62.7% (both P <0.05), respectively. The ECoG power also declined to 85% and 50% in the cooled cortex, and to 94% and 49% in the mirror cortex by the cooling at 15 and 5°C, respectively. The spikes regained in the middle of the cooling period at 15°C and in the late period at 5°C. Seizure-free durations during the 10-min periods of cooling at 15 and 5°C lasted for 4.1 ± 2.2 and 5.9 ± 1.1 min, respectively. Although temperature-dependent seizure alleviation was observed, the effect of local cortical cooling on GMSs was limited compared with the effect of local cooling of the epileptic focus on GSMs.

GABA and Gap Junctions in the Development of Synchronized Activity in Human Pluripotent Stem Cell-Derived Neural Networks

The electrical activity of the brain arises from single neurons communicating with each other. However, how single neurons interact during early development to give rise to neural network activity remains poorly understood. We studied the emergence of synchronous neural activity in human pluripotent stem cell (hPSC)-derived neural networks simultaneously on a single-neuron level and network level. The contribution of gamma-aminobutyric acid (GABA) and gap junctions to the development of synchronous activity in hPSC-derived neural networks was studied with GABA agonist and antagonist and by blocking gap junctional communication, respectively. We characterized the dynamics of the network-wide synchrony in hPSC-derived neural networks with high spatial resolution (calcium imaging) and temporal resolution microelectrode array (MEA). We found that the emergence of synchrony correlates with a decrease in very strong GABA excitation. However, the synchronous network was found to consist of a heterogeneous mixture of synchronously active cells with variable responses to GABA, GABA agonists and gap junction blockers. Furthermore, we show how single-cell distributions give rise to the network effect of GABA, GABA agonists and gap junction blockers. Finally, based on our observations, we suggest that the earliest form of synchronous neuronal activity depends on gap junctions and a decrease in GABA induced depolarization but not on GABAA mediated signaling.

Antioxidant-mediated neuro-protective and GABAergic calming effect of Stephania japonica

Stephania japonica, a tropically-habituated plant is widely distributed in Bangladesh. Traditionally, it has been used in the treatment of inflammation, asthma, fever, sleep disturbance, painful conditions, and rheumatism. However, scientific evidence of its biological activities are very limited. This study evaluated neuroprotctivity along with a possible anxiolytic-like effect of the methanol leaf extract of S. japonica (MSJ). The antioxidant test was performed by using the scavenging capacity of hydroxyl (●OH) and nitric oxide (●OH) radicals; and an inhibition of lipid peroxidation assay. In vitro, egg albumin denaturation (IELD) and anti-acetylcholinesterase (anti-AChE) tests were performed to evaluate the anti-inflammatory and anti-cholinesterase activity, respectively. Additionally, a possible anxiolytic action of the MSJ was investigated in Swiss mice by taking diazepam (DZP) and flumazenil (FLU) as gamma amino butyric acid (GABA) receptor agonist and antagonist, respectively. The MSJ concentration (50-200 µg/mL)/dose (50-200 mg/kg, oral)-dependently exhibited antioxidant, anti-inflammatory, anti-AChE and anxiolytic-like effects. The MSJ also increased the activities of the standards used in antioxidant and anti-AChE (trolox), anti-inflammatory (acetyl salicylic acid), and anxiolytic (DZP: agonist) test. The MSJ exhibited antioxidant and anti-inflammatory activities. It also potentiated the action of DZP, while antagonizing the effect of the FLU, suggesting a possible GABAergic, DZP-agonistic anxiolytic-like action in experimental animals. S. japonica may be one of the good sources of neuroprotective phytochemicals.

Intra-hippocampal microinjection of oxytocin produced antiepileptic effect on the pentylenetetrazol-induced epilepsy in rats.

In addition to its role as a circulating hormone, oxytocin can also act as a neurotransmitter and a neuromodulator within the brain. In this study, we investigated the intra-hippocampal effect of oxytocin on an experimental seizure model induced by pentylenetetrazole (PTZ) in rats. We also used atosiban (oxytocin antagonist), diazepam and flumazenil (gamma-aminobutyric acid or GABA-benzodiazepine receptor agonist and antagonist, respectively) to clarify the involved mechanism. In ketamine-xylazine anesthetized rats, the right and left sides of the dorsal hippocampus (CA1) were implanted with two guide cannulas. Epileptic behaviors were induced by intraperitoneal (ip) injection of PTZ (60mg/kg), and the latency time to onset of first myoclonic jerk, and the duration of epileptic seizures were determined for 30min. Intra-hippocampal microinjections of oxytocin at doses of 10 and 20ng/site, diazepam (100 and 200ng/site) and co-administration of their ineffective doses significantly (p<0.01) increased the onset of first myoclonic jerk and decreased duration of epileptic seizure. Antiepileptic effects of oxytocin (20ng/site) were inhibited by atosiban (20 and 40ng/site) and flumazenil (100 and 200ng/site) pretreatments. On the other hand, prior administration of flumazenil (100 and 200ng/site) and atosiban (20 and 40ng/site) prevented the antiepileptic effects induced by diazepam (100 and 200ng/site). The results of the present study showed that at the level of the hippocampus oxytocin suppressed the severity of epileptic behaviors. A hippocampal GABA-benzodiazepine receptor mechanism may be involved in antiepileptic effect of oxytocin.

Mosquitocidal Activity and Mode of Action of the Isoxazoline Fluralaner.

Mosquitoes, such as Aedes aegypti and Anopheles gambiae, are important vectors of human diseases. Fluralaner, a recently introduced parasiticide, was evaluated as a mosquitocide in this study. On Ae. aegypti and An. gambiae fourth-instar larvae, fluralaner had 24-h LC50 (lethal concentration for 50% mortality) values of 1.8 ppb and 0.4 ppb, respectively. Following topical application to adult Ae. aegypti, fluralaner toxicity reached a plateau in about 3 days, with 1- and 3-day LD50 (lethal dose for 50% mortality) values of 1.3 ng/mg and 0.26 ng/mg, suggesting a slowly developing toxicity. Fipronil outperformed fluralaner by up to 100-fold in adult topical, glass contact, and feeding assays on Ae. aegypti. These data show that fluralaner does not have exceptional toxicity to mosquitoes in typical exposure paradigms. In electrophysiological recordings on Drosophila melanogaster larval central nervous system, the effectiveness of fluralaner for restoring nerve firing after gamma-aminobutyric acid (GABA) treatment, a measure of GABA antagonism, was similar in susceptible Oregon-R and cyclodiene-resistant rdl-1675 strains, with EC50 (half maximal effective concentration) values of 0.34 µM and 0.29 µM. Although this finding suggests low cross resistance in the presence of rdl, the moderate potency, low contact activity, and slow action of fluralaner argue against its use as an adult mosquitocide for vector control.

Cloaked Caged Compounds: Chemical Probes for Two-Photon Optoneurobiology.

Caged neurotransmitters, in combination with focused light beams, enable precise interrogation of neuronal function, even at the level of single synapses. However, most caged transmitters are, surprisingly, severe antagonists of ionotropic gamma-aminobutyric acid (GABA) receptors. By conjugation of a large, neutral dendrimer to a caged GABA probe we introduce a "cloaking" technology that effectively reduces such antagonism to very low levels. Such cloaked caged compounds will enable the study of the signaling of the inhibitory neurotransmitter GABA in its natural state using two-photon uncaging microscopy for the first time.

Memory impairment due to fipronil pesticide exposure occurs at the GABAA receptor level, in rats

Fipronil (F) a pesticide considered of second generation cause various toxic effects in target and non-target organisms including humans in which provoke neurotoxicity, having the antagonism of gamma-amino butyric acid (GABA) as their main mechanism for toxic action. GABAergic system has been involved in processes related to the memory formation and consolidation. The present work studied the importance of GABA to the mechanisms involved in the very early development of fipronil-induced memory impairment in rats. Memory behavior was assessed using new object recognition task (ORT) and eight radial arm maze task (8-RAM) to study effects on cognitive and spatial memory. Locomotor behavior was assessed using open field task (OF). The dose of fipronil utilized was studied through a pilot experiment. The GABA antagonist picrotoxin (P) was used to enhance fipronil effects on GABAergic system. Fipronil or picrotoxin decrease memory studied in ORT and 8-RAM tasks. Additionally, F and P co-exposure enhanced effects on memory compared to controls, F, and P, suggesting strongly a GABAergic effect. Weight gain modulation and fipronil in blood were utilized as animal's intoxication indicators. In conclusion, here we report that second-generation pesticides, such as fipronil, can have toxic interactions with the CNS of mammals and lead to memory impairment by modulating the GABAergic system.

Carbamazepine Induced Ebstein-Barr Virus Reactivation: A Rare Manifestation of Anticonvulsant Hypersensitivity Syndrome

Carbamazepine (CBZ) is an antiepileptic drug which has multiple mechanisms of action including stabilization of the inactivated stage of the voltage-gated sodium channels, potentiating gamma-amino butyric acid (GABA) receptors as a GABA antagonist, as well as the serotonin releasing affect. It is effective in neuropathic pain syndromes such as post-herpetic neuralgia and trigeminal neuralgia, as well as epilepsy. We presented a 29-year-old female patient with the diagnosis of trigeminal neuralgia (TN) who experienced a reactivation of the latent Ebstein-Barr Virus (EBV) infection in terms of anticonvulsant hypersensitivity syndrome after CBZ use, who gave her approval to publish her data. Since the clinical and serological findings of EBV re-infection resolved after the discontinuation of the drug, this clinical and serological manifestation was attributed to CBZ. Since common side-effects of CBZ are drowsiness, dizziness, headaches, skin reactions, cognitive dysfunctions, we reported an activation of EBV infection due to CBZ consumption as a rare side-effect of the drug.

The sublethal effects of endosulfan on the circadian rhythms and locomotor activity of two sympatric parasitoid species

The organochlorine insecticide endosulfan is dispersed worldwide and significantly contributes to environmental pollution. It is an antagonist of the neurotransmitter gamma-aminobutyric acid (GABA), which is also indirectly involved in photoperiodic time measurement. In this study, we show that endosulfan at a dose as low as LC 0.1 modified the rhythm of locomotor activity of two sympatric parasitoid species, Leptopilina boulardi and Leptopilina heterotoma. The insecticide strongly increased the nocturnal activity of both species and synchronized their diurnal activity; these activities were not synchronized under control conditions. Parasitoids are important species in ecosystems because they control the populations of other insects. In this paper, we discuss the possible consequences of these sublethal effects and highlight the importance of such effects in evaluating the consequences of environmental pollution due to insecticides.

Determination of bicuculline in rat plasma by liquid chromatography mass spectrometry and its application in a pharmacokinetic study

Bicuculline, a phthalide isoquinoline alkaloid is of current interest as an antagonist of gamma-aminobutyric acid (GABA). A simple and sensitive liquid chromatography mass spectrometry method for determination of bicuculline in rat plasma was developed over the range of 5-500ng/mL. After addition of midazolam as internal standard, protein precipitation with acetonitrile-methanol (9:1, v/v) was used as sample preparation. Chromatographic separation was achieved on a Zorbax SB-C18 (2.1mm×150mm, 5μm) column with acetonitrile -0.1% formic acid in water as mobile phase with gradient elution. Electrospray ionization (ESI) source was applied and operated in positive ion mode; selective ion monitoring (SIM) mode was used for quantification using target fragment ions m/z 368 for bicuculline and m/z 326 for the IS. Linear calibration was obtained with correlation coefficients r>0.99. The CV of the precision measurements was less than 13%. The accuracy of the method ranged from 93.6% to 100.5%. Mean recoveries of bicuculline in plasma were in the range of 80.5-91.8%. The method was successfully applied to the pharmacokinetic study after gavage administration of 15mg/kg bicuculline in rats.

Ionotropic GABA Receptors and Distal Retinal ON and OFF Responses.

In the vertebrate retina, visual signals are segregated into parallel ON and OFF pathways, which provide information for light increments and decrements. The segregation is first evident at the level of the ON and OFF bipolar cells in distal retina. The activity of large populations of ON and OFF bipolar cells is reflected in the b- and d-waves of the diffuse electroretinogram (ERG). The role of gamma-aminobutyric acid (GABA), acting through ionotropic GABA receptors in shaping the ON and OFF responses in distal retina, is a matter of debate. This review summarized current knowledge about the types of the GABAergic neurons and ionotropic GABA receptors in the retina as well as the effects of GABA and specific GABAA and GABAC receptor antagonists on the activity of the ON and OFF bipolar cells in both nonmammalian and mammalian retina. Special emphasis is put on the effects on b- and d-waves of the ERG as a useful tool for assessment of the overall function of distal retinal ON and OFF channels. The role of GABAergic system in establishing the ON-OFF asymmetry concerning the time course and absolute and relative sensitivity of the ERG responses under different conditions of light adaptation in amphibian retina is also discussed.

Enduring Effects of Adolescent Drug Exposure

Enduring Effects of Adolescent Drug Exposure

Functional Role of Amino Acid Neurotransmitters on Spontaneous Muscular Activity of Paramphistomum cervi from Ruminants

The neuropharmacological studies of Paramphistomum cervi were conducted ex vivo by extracellular electrical activity. The instrumentation and methodology described in the experiment, quantitatively measure the extracellular electrical potentials associated with motor activity and provide highly sensitive objective techniques for studying the effects of antitrematodal compounds and for evaluating P. cervi as a model for neuropharmacological investigations. In the present investigation, the effects of various neuropharmacological agents viz. amino acid neurotransmitters [l-glutamate, gamma-amino butyric acid (GABA), glycine], GABA antagonists (picrotoxin and bicuculline) and glycine antagonist (strychnine) were investigated on the spontaneous muscular activity of P. cervi. l-Glutamate, an excitatory neurotransmitter produced significant increase in amplitude and baseline tension at 10−7–10−5 M concentration, and frequency at 10−4–10−3 M concentration. Glycine, an inhibitory neurotransmitter on the other hand, produced significant reduction of amplitude at 10−6–10−3 M concentration and baseline tension and frequency at 10−3 M concentration. On the contrary, strychnine an antagonist of glycine produced significant increase of amplitude, baseline tension and frequency at 10−6–10−3 M concentration. Another inhibitory neurotransmitter, GABA mediated significant reduction in amplitude and baseline tension at 10−3 M concentration. Picrotoxin, being an antagonist of GABA produced marked significant increase in amplitude (g) and baseline tension (g) at 10−7–10−3 M concentration with an increase in frequency at 10−4 and 10−3 M concentration. In the present study another GABAA antagonist, bicuculline was found to be non responsive in P. cervi.

Mechanisms of seizure propagation in 2-dimensional centre-surround recurrent networks.

Understanding how seizures spread throughout the brain is an important problem in the treatment of epilepsy, especially for implantable devices that aim to avert focal seizures before they spread to, and overwhelm, the rest of the brain. This paper presents an analysis of the speed of propagation in a computational model of seizure-like activity in a 2-dimensional recurrent network of integrate-and-fire neurons containing both excitatory and inhibitory populations and having a difference of Gaussians connectivity structure, an approximation to that observed in cerebral cortex. In the same computational model network, alternative mechanisms are explored in order to simulate the range of seizure-like activity propagation speeds (0.1–100 mm/s) observed in two animal-slice-based models of epilepsy: (1) low extracellular , which creates excess excitation and (2) introduction of gamma-aminobutyric acid (GABA) antagonists, which reduce inhibition. Moreover, two alternative connection topologies are considered: excitation broader than inhibition, and inhibition broader than excitation. It was found that the empirically observed range of propagation velocities can be obtained for both connection topologies. For the case of the GABA antagonist model simulation, consistent with other studies, it was found that there is an effective threshold in the degree of inhibition below which waves begin to propagate. For the case of the low extracellular model simulation, it was found that activity-dependent reductions in inhibition provide a potential explanation for the emergence of slowly propagating waves. This was simulated as a depression of inhibitory synapses, but it may also be achieved by other mechanisms. This work provides a localised network understanding of the propagation of seizures in 2-dimensional centre-surround networks that can be tested empirically.