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C L Faingold

Publications and source records attributed to C L Faingold.

At least 37 records · Page 2Linked to original sources
PubMed1996

Decreased GABA effectiveness in the inferior colliculus neurons during ethanol withdrawal in rats susceptible to audiogenic seizures.

The inferior colliculus (IC) is the initiation site in the neuronal network for audiogenic seizure (AGS) in rats undergoing ethanol withdrawal (ETX). Considerable evidence supports a role of gamma-aminobutyric acid (GABA)-mediated inhibition in normal acoustic processing in the IC. Altered GABA-mediated inhibition in the IC is suggested to be important in the control of AGS initiation. The present study used microiontophoresis to examine the effectiveness of GABA on acoustically-evoked neuronal responses in the central nucleus of the IC (ICc). GABA effectiveness was compared in normal controls and a group of animals displaying high audiogenic seizure susceptibility (100% AGS) (HAGS), and a group exhibiting a low (mean, 33%) incidence of AGS (LAGS). Ethanol was administered for 4 days in three daily doses (9-15 g/kg/day) sufficient to maintain a moderate degree of intoxication. Tonic-clonic seizures were observed in HAGS animals, while LAGS rats exhibited less severe seizures, consisting primarily of wild running. Iontophoretic application of GABA consistently inhibited ICc neuronal firing in controls and in animals undergoing ETX. However, the mean dose (current) of GABA required to produce a 50% reduction of the ICc neuronal firing in the HAGS group was nearly twice that of the control animals. The mean dose of GABA for 50% inhibition in the LAGS group was about one-half that of the control group. Both of these differences were statistically significant. These data suggest that decreased GABA effectiveness in the IC neurons of HAGS susceptible animals is an important mechanism contributing to the propagation of severe AGS seen during ETX in these animals.

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PubMed1996

Repetitive audiogenic seizures cause an increased acoustic response in inferior colliculus neurons and additional convulsive behaviors in the genetically-epilepsy prone rat.

Previous studies indicate that daily repetition of audiogenic seizures (AGS) leads to audiogenic 'kindling' with increased seizure duration and additional seizural behaviors. The present study examined the neuronal correlates of this phenomenon. Extracellular single neuron firing and concomitant convulsive behaviors associated with 14 repetitive AGS were evaluated in the genetically epilepsy-prone rat severe seizure strain (GEPR-9). An increase in the number of acoustically-evoked action potentials in neurons of the central nucleus of inferior colliculus (ICc) was observed by the second day of AGS repetition, and peaked at day four. The ICc responses remained at similar enhanced level through day 14. ICc neuronal responses were completely absent for approximately two min post-ictally after a single AGS in all animals, but 80% of the animals undergoing repetitive AGS consistently exhibited neuronal firing in this post-ictal period. Post-tonic clonus and an increased duration of post-ictal behavioral depression were also observed with repetitive AGS. The increased ICc neuronal firing was observed prior to the appearance of the post-tonic clonus component of repetitive AGS. This suggests that the ICc neuronal firing increase may subserve, at least, the initial increase in AGS severity. However, changes in neuronal firing in nuclei of the neuronal network for AGS efferent to the ICc may be responsible for the increased AGS severity that occurs after the fourth day of AGS repetition.

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PubMed1996

Increased responsiveness and failure of habituation in neurons of the external nucleus of inferior colliculus associated with audiogenic seizures of the genetically epilepsy-prone rat.

Initiation of audiogenic seizures (AGS) emanates from the inferior colliculus (IC) to other IC subnuclei in the genetically epilepsy-prone rat (GEPR). The external nucleus of IC (ICx) is a suggested site of convergence of the auditory output onto the sensorimotor integration network components for AGS in the brainstem. Neuronal firing was recorded from the ICx of the awake, freely moving GEPR and normal Sprague-Dawley rats using microwire electrodes in the present study. Auditory stimuli consisted of 12-kHz tones (100 ms, 5-ms rise-fall at rates of 1/4s, 1/2s, and 1/s). AGS incidence in the GEPR is highest at 12 kHz. In the GEPR, ICx neuronal responses to acoustic stimuli were significantly greater than those seen in normal rats. This increased ICx firing was observed at relatively high acoustic intensities (> 80 dB SPL), which are near the threshold for AGS induction. Repetition-induced response attenuation (habituation) is commonly observed in ICx neurons, which appears to be overcome in the GEPR during AGS initiation. Tonic, acoustically evoked ICx neuronal firing was observed just prior to wild running. ICx firing was suppressed during the tonic and postictal phases of AGS. Recovery of ICx responses occurred when the animal regained postural control. Abnormal, intense output has previously been observed in the GEPR IC central nucleus (ICc) neurons. The neuronal firing pattern changes observed in the ICx in the present study may result from this intense ICc output. Diminished efficacy of GABA, which has been observed in several regions of the GEPR brain, including the IC, in a number of previous studies, may be involved in the exaggerated ICx responses to acoustic stimuli in the GEPR. Participation of the ICx in the AGS neuronal network may be subserved by this acoustic hyperresponsiveness.

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PubMed1995

Pontine reticular formation neurons exhibit a premature and precipitous increase in acoustic responses prior to audiogenic seizures in genetically epilepsy-prone rats.

The genetically epilepsy-prone rat (GEPR-9) exhibits elevated seizure sensitivity and audiogenic seizures (AGS). The pontine reticular formation (PRF) is implicated in the neuronal network for AGS in the GEPR-9. The present study examined PRF neuronal firing and convulsive behavior simultaneously in the GEPR-9. Chronically implanted microwire electrodes in PRF allowed single neuronal responses and behavior to be examined in freely-moving rats. PRF neurons in the GEPR-9 exhibit precipitous intensity-evoked increases at a significantly lower (approx. 15 dB SPL) intensity than normal Sprague-Dawley rats. PRF neurons in the GEPR-9 also exhibit increased auditory response latencies. At the onset of AGS (wild running) the firing rate of PRF neurons increased, and the rate of PRF firing increased dramatically as the tonic phase of the seizure began. During post-ictal depression the rate of PRF neuronal firing slowed, gradually returning to normal. This pattern of PRF periseizural neuronal firing changes differ dramatically in pattern and temporal characteristics from those previously observed in inferior colliculus (IC). The IC serves as the AGS initiation site. IC neurons show extensive firing increases prior to and during the initial wild running, silence during the tonic and post-ictal phases, and gradual recovery of responses thereafter. The changes in PRF neuronal firing pattern suggest that the PRF may play a major role in the generation of the tonic phase of AGS. The premature onset of the precipitous rise in PRF neuronal firing suggests that the influence of the IC on PRF neurons may be magnified in association with AGS susceptibility. The PRF neuronal firing increases observed in the present study coupled with previous observation of AGS blockade by PRF microinjections in the GEPR-9 further support an important role of the PRF in the propagation of AGS in the GEPR-9. The mechanisms of PRF firing elevation may also be relevant in other seizure models in which the brain-stem reticular formation is implicated.

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PubMed1995

Ethanol withdrawal induces increased firing in inferior colliculus neurons associated with audiogenic seizure susceptibility.

Ethanol withdrawal (ETX) in ethanol-dependent rats results in susceptibility to seizures, including generalized tonic-clonic audiogenic seizures (AGS). The inferior colliculus (IC) is strongly implicated in AGS initiation during ETX, but IC neuronal mechanisms subserving AGS are unclear. The present study examined IC (central nucleus) single neuronal firing during repeated (4 day) intragastric ethanol administration and during ETX. This involved microwire electrodes implanted chronically into freely moving rats and acoustic stimulation in intensities up to 105 dB SPL. During initial ethanol administration the animals were stuporous, and IC spontaneous neuronal firing and acoustically evoked firing at high stimulus intensities were significantly reduced. This firing reduction is consistent with the action of ethanol to enhance gamma-aminobutyric acid (GABA)-mediated inhibition, which is prominent in IC neurons at high stimulus intensities. During ETX the animals were agitated, and spontaneous IC neuronal firing and acoustically evoked firing at all stimulus intensities were significantly increased during the period of AGS susceptibility. Previous studies indicate that IC neuronal responses are tightly regulated by GABA and glutamate. The IC firing increases during ETX in the present study may involve the down-regulation of GABAA receptors and supersensitivity of glutamate receptors reported to occur during ETX. Previous studies also indicate that focal blockade of GABAA receptors or activation of glutamate receptors produces AGS susceptibility in normal rats. Therefore, the IC neuronal firing increases observed in the present study may play a critical role in initiation of AGS during ethanol withdrawal.

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PubMed1994

Increased responsiveness of pontine reticular formation neurons associated with audiogenic seizure susceptibility during ethanol withdrawal.

Susceptibility to audiogenic seizures (AGS) is observed during ethanol withdrawal (ETX). The pontine reticular formation (PRF) is implicated in the propagation pathway for AGS during ETX. The present study examined the changes in single PRF neuronal firing patterns produced by ethanol and during ETX following repeated intragastrically administered ethanol. Microwire electrode bundles were implanted into PRF and single neuronal responses in freely moving rats were examined. During initial ethanol administration the animals were stuporous, and spontaneous and acoustically-evoked PRF neuronal firing were reduced significantly. During ETX the animals were susceptible to AGS and displayed agitated and irritable behavior. At this time a significant increase in spontaneous and acoustically-evoked PRF neuronal firing was observed. Repetition-induced response attenuation (habituation) of PRF neuronal responses was significantly diminished during ETX, leading to an exaggerated acoustic startle response, which may be a physiological basis for AGS. Previous reports indicate that ethanol enhances the effects of GABA and decreases the effects of glutamate. The PRF neuronal firing increases during EXT in the present study may involve the down-regulation of GABAA receptors and supesensitivity of glutamate receptors reported to occur during ETX, which could contribute to AGS susceptibility. The PRF neuronal firing increases observed in the present study in concord with previous observation of AGS blockade by PRF microinjections during ETX further support an important role of this brain region in the propagation of AGS during ethanol withdrawal.

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PubMed1994

Inferior colliculus neuronal membrane and synaptic properties in genetically epilepsy-prone rats.

Previous studies using single-unit recording techniques have shown that the inferior colliculus is critical for audiogenic seizure initiation in genetically epilepsy-prone rats (GEPR). In order to investigate cellular abnormalities that may be important in causing audiogenic seizure susceptibility, intracellular recordings were made from neurons of inferior colliculus dorsal cortex (ICd) in a GEPR variety that exhibits severe audiogenic seizures (GEPR-9). GEPR neuronal membrane and synaptic properties were compared to those of normal Sprague-Dawley rats (SD), the strain from which GEPR were derived. We found six electrophysiological differences between GEPR and normal SD ICd neurons, all of which could promote seizures in GEPR. (1) Input resistance was higher in GEPR than in normal ICd neurons. (2) Threshold for repetitive action potential firing was closer to resting membrane potential in GEPR ICd neurons. (3) GEPR neurons showed faster repetitive spike firing than normal SD neurons. (4) Anode break spikes occurred at the offset of a hyperpolarizing pulse more often in GEPR than in normal SD neurons. (5) Stimulation of the commissure of the inferior colliculus caused synaptic paired pulse inhibition in normal ICd neurons, but paired pulse facilitation was always observed in GEPR neurons. (6) In GEPR, a large epileptiform depolarizing event could be elicited by strong electrical stimulation of the commissure of the inferior colliculus. In normal SD rats, similar epileptiform activity was seen only after application of bicuculline or NMDA. Our results suggest that both abnormal neuronal membrane properties and altered synaptic transmission are likely to contribute to seizure predisposition and audiogenic seizure initiation in GEPR.

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PubMed1994

GABA in the inferior colliculus plays a critical role in control of audiogenic seizures.

Previous studies have implicated a decreased efficacy of GABA as an important defect subserving the audiogenic seizures of the genetically epilepsy-prone rat (GEPR-9). The inferior colliculus (IC) is a critical site for audiogenic seizure (AGS) initiation, and the pontine reticular formation (PRF) is implicated in the propagation of AGS and in other generalized seizure models. The present study observed that microinjection of baclofen, a GABA-B receptor agonist, into IC protects against AGS, and blockade of the breakdown of endogenous GABA by gabaculine, a GABA transaminase inhibitor, increased GABA levels and blocked AGS susceptibility in the GEPR-9. Microinjection of baclofen or gabaculine into the PRF reduced AGS severity, but the doses required were considerably greater and the degree of anticonvulsant effect was less. Uptake of [3H]GABA into GEPR-9 synaptosomes from the IC is significantly increased as compared to normal, which could contribute to the diminished effectiveness of GABA in the GEPR-9. Previous studies indicate that GABA-A receptor agonists block AGS with IC microinjection, and recent data indicate that blockade of GABA uptake in this nucleus significantly reduced AGS severity. These data taken together strongly support the critical importance of the defect in GABA function in the IC in modulating susceptibility to audiogenic seizure initiation in the GEPR-9.

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PubMed1994

Blockade of GABA uptake with tiagabine inhibits audiogenic seizures and reduces neuronal firing in the inferior colliculus of the genetically epilepsy-prone rat.

Tiagabine is a new anticonvulsant drug that blocks the uptake of GABA, prolonging the action of this inhibitory transmitter. In the present study the effects of systemically administered tiagabine [30 mg/kg, ip (ED50)] were examined on audiogenic seizure (AGS) severity and neuronal firing in the inferior colliculus (IC) in the freely moving genetically epilepsy-prone rat (GEPR-9). The IC is known to be critical to AGS initiation. The effects of focal microinjection of tiagabine into the IC were also examined. Bilateral focal microinjection of tiagabine into the IC significantly reduced seizure severity in the GEPR-9. Systemically administered tiagabine also produced a significant reduction in seizure severity in the GEPR-9. Tiagabine produced a reduction in IC (central nucleus) neuronal firing, which was significant only at high acoustic intensities (90-105 dB), concomitant with the considerable reduction in seizure severity. These data are consistent with enhancement by tiagabine of gamma-aminobutyric acid (GABA)-mediated inhibition in IC, which is most prominent at high acoustic intensities. The time course of the reduction in neuronal firing of IC neurons paralleled the reduction in seizure severity. Previous studies have shown that two forms of GABA-mediated inhibition (intensity-induced and offset inhibition) in IC neurons are most prominent at high stimulus intensities, which are required to induce AGS. The blockade of GABA uptake by tiagabine may act to inhibit audiogenic seizures, in part, by intensifying these naturally occurring forms of acoustically evoked inhibition in inferior colliculus neurons.

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PubMed1994

Loss of synaptic inhibition during repetitive stimulation in genetically epilepsy-prone rats (GEPR).

Genetically epilepsy-prone rats (GEPR) are an animal model of generalized motor seizures. The underlying causes of the predisposition to seizures in GEPR have not been fully determined. The brainstem auditory system is critical for audiogenic seizures in GEPR, and neurophysiological abnormalities have been observed in these areas, but recent evidence suggests that non-auditory brain areas may also be abnormal. This may account for the lowered threshold in GEPR for various non-audiogenic seizures. Because the normal responses of the hippocampal Schaffer collateral/CA1 synapse are relatively well understood, we studied single and repetitive synaptic responses in hippocampal slices of GEPR in vitro. Our hypothesis was that altered excitatory or inhibitory synaptic transmission may contribute to GEPR non-audiogenic seizure predisposition. We recorded extracellular EPSPs, population spikes, and afferent volleys in hippocampal area CA1, and compared GEPR responses to those of Sprague-Dawley (SD) rats, the strain from which GEPR were derived. GEPR responses to single synaptic stimuli were not significantly different from SD. The second of a pair of closely spaced EPSPs or population spikes was larger in both GEPR and SD (paired pulse facilitation), but the magnitude of population spike facilitation was significantly increased in GEPR. Short trains of four stimuli caused inhibition of population spike firing in SD, an effect that was much reduced in GEPR. When SD slices were treated with bicuculline, a GABAA receptor antagonist, enhanced paired pulse facilitation and loss of inhibition during trains of stimuli were seen, similar to the patterns seen in GEPR.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1994

Seizures during ethanol withdrawal are blocked by focal microinjection of excitant amino acid antagonists into the inferior colliculus and pontine reticular formation.

Physical dependence on ethanol can result in seizure susceptibility during ethanol withdrawal. In rats, generalized tonic-clonic seizures are precipitated by auditory stimulation during the ethanol withdrawal syndrome. Excitant amino acids (EAAs) are implicated as neurotransmitters in the inferior colliculus and the brain stem reticular formation, which play important roles in the neuronal network for genetic models of audiogenic seizures (AGSs). Ethanol blocks the actions of EAAs in various brain regions, including the inferior colliculus. In this study, dependence was produced by intragastric administration of ethanol for 4 days. During ethanol withdrawal, AGSs were blocked by systemic administration of competitive or noncompetitive NMDA antagonists 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) or dizocilpine (MK-801). Focal microinjections of NMDA or non-NMDA antagonists into the inferior colliculus or the pontine reticular formation also inhibited AGSs. MK-801 was the most potent anticonvulsant systemically. When injected into the inferior colliculus, CPP had a more potent anticonvulsant effect than either MK-801 or the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. The inferior colliculus was more sensitive than the pontine reticular formation to the anticonvulsant effects of both competitive NMDA and non-NMDA antagonists. The results of the present support the idea that continued ethanol administration may lead to development of supersensitivity to the action of EAAs in inferior colliculus and pontine reticular formation neurons. This may be a critical mechanism subserving AGS susceptibility during ethanol withdrawal.

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PubMed1993

Noncompetitive and competitive NMDA antagonists exert anticonvulsant effects by actions on different sites within the neuronal network for audiogenic seizures.

Excitant amino acids are implicated in audiogenic seizure (AGS) susceptibility in the genetically epilepsy-prone rat (GEPR). In the present study systemic administration of NMDA receptor antagonists significantly decreased AGS severity in the GEPR. Systemic administration of the competitive NMDA antagonists 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP) and 2-amino-7-phosphonoheptanoic acid and the non-competitive antagonist dizocilpine (MK-801) were effectively anticonvulsant in the GEPR. The inferior colliculus is the most critical nucleus for AGS initiation in the GEPR and an excitant amino acid is implicated as an important excitatory transmitter in inferior colliculus neurons. Systemically administered CPP significantly reduced inferior colliculus neuronal firing in the normal behaving rat and the GEPR concurrently with blockade of AGS and this effect occurred at nearly all sound intensities tested. Systemic administration of MK-801, while effective in blocking AGS, produced no consistent change in inferior colliculus neuronal firing, which is consistent with its very low potency in blocking AGS with bilateral microinjection into the inferior colliculus. These findings suggest that an important action of competitive, but not noncompetitive, NMDA antagonists is on brain stem auditory nuclei, especially the inferior colliculus, that are critical to AGS. MK-801 appears to exert its anticonvulsant effects in AGS network sites beyond the inferior colliculus. These findings and recent inferior colliculus slice studies suggest that NMDA receptors in inferior colliculus may have quantitatively different properties from those in other brain regions. These differences in NMDA receptor function in inferior colliculus may reflect NMDA receptor heterogeneity observed in binding studies.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1993

Stimulation or blockade of the dorsal nucleus of the lateral lemniscus alters binaural and tonic inhibition in contralateral inferior colliculus neurons.

Recent studies have demonstrated that several specific types of acoustically-evoked GABA-mediated inhibition occur in neurons of the central nucleus of inferior colliculus (ICc). The dorsal nucleus of the lateral lemniscus (DNLL) provides a major GABAergic projection to ICc. The present study examined the effects of electrical or chemical stimulation or reversible blockade within the DNLL on the discharge characteristics of ICc neurons in anesthetized rats. Microinjection of a local anesthetic (lidocaine) or a GABA-A agonist (THIP) via a cannula placed into DNLL reversibly blocked acoustically-evoked binaural inhibition and increased spontaneous firing in most contralateral ICc neurons. Trains of electrical pulses or microinjection of the excitant amino acid, kainate, into DNLL resulted in reduced acoustically-evoked firing, which was similar to binaural inhibition, in most contralateral ICc neurons examined. The effects of DNLL electrical stimulation were reversibly blocked by microinjection of THIP into the stimulation site, suggesting that the effect of the electrical stimulation is mediated by direct effects on cell bodies of DNLL neurons. These data support the idea that contralateral GABAergic input from the DNLL is inhibitory to ICc neurons. Thus, binaural inhibition and tonic inhibition in ICc neurons may be mediated, in part, by the GABAergic projection from the contralateral DNLL.

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PubMed1992

Repetition of audiogenic seizures in genetically epilepsy-prone rats induces cortical epileptiform activity and additional seizure behaviors.

Repetition of seizures appears to increase severity in a number of seizure models, but the nature of these severity increases has not been elucidated in naturally occurring genetic epilepsy models. The genetically epilepsy-prone rat (GEPR) is highly susceptible to many seizure provoking stimuli, and high intensity acoustic stimuli induce audiogenic seizures (AGS). The role of forebrain structures in AGS in the GEPR has not been clear, and the presence of cortical epileptiform EEG activity in the GEPR is controversial. The present study examined the effects of 21 daily AGS repetitions on behavior and EEG activity recorded from the cortex of two GEPR substrains that exhibit moderate (GEPR-3) or severe AGS (GEPR-9). The results indicated that AGS repetition induced seizure severity increases in both GEPR substrains and resulted in prominent cortical epileptiform EEG activity. The AGS behavioral patterns remained distinctly different in the two substrains throughout seizure repetition. In each substrain a different additional behavioral phase was expressed; the GEPR-9 exhibited post-tonic clonus, and the GEPR-3 exhibited facial and forelimb clonus. These findings indicate that seizure repetition results in expansion of the neuronal network subserving AGS to involve forebrain structures. The medial geniculate body and amygdala appear to be part of this expanded network, and long-term potentiation, which was reported in the pathway between the latter brain structures, may be involved. These data suggest that recruitment of forebrain structures into the AGS neuronal network appears to be essential for production of the additional ictal behaviors evoked by AGS repetition.

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PubMed1992

Glutamate in the inferior colliculus plays a critical role in audiogenic seizure initiation.

Alterations of excitant amino acid (EAA) action are implicated in seizure susceptibility in the genetically epilepsy-prone rat (GEPR). The inferior colliculus (IC) is critical for audiogenic seizure (AGS) initiation in the GEPR. The present study observed that bilateral microinjection into the IC of L-canaline, a glutamate synthesis inhibitor, decreased AGS severity in the GEPR and also decreased potassium-evoked release of glutamate from IC slices. Bilateral microinjection of NMDA receptor antagonists, 2-amino-7-phosphonoheptanoate (AP7) or 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP) into IC blocked AGS, and an antagonist at non-NMDA EAA receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), also blocked AGS. NMDA receptor antagonists were 5-200 times more effective than CNQX. Microinjection of a non-competitive NMDA receptor antagonist, dizocilpine (MK-801), into IC had little effect except with very high doses. Microinjection of CPP or AP7 into the IC blocked AGS at considerably lower doses as compared to pontine reticular formation (PRF). However, MK-801 attenuated AGS when microinjected into PRF at doses that were ineffective in IC. Systemically administered CPP blocked AGS and significantly reduced IC neuronal firing in the behaving GEPR, suggesting an important action of systemically administered NMDA receptor antagonists on brainstem auditory nuclei critical to AGS. The present results support a critical role for glutamate acting, in part, through NMDA receptors in IC in initiation of AGS.

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PubMed1991

Loss of intensity-induced inhibition in inferior colliculus neurons leads to audiogenic seizure susceptibility in behaving genetically epilepsy-prone rats.

The genetically epilepsy-prone rat (GEPR) exhibits elevated seizure sensitivity and audiogenic seizures (AGS). The inferior colliculus (IC) is the most critical brain region for AGS initiation. The present study evaluated IC neuronal firing and convulsive behavior simultaneously in freely moving GEPRs. High intensity acoustic stimulation produces neuronal firing reductions (intensity-induced inhibition) in about 50% of IC neurons in normal rats. However, in GEPR IC neurons, intensity-induced inhibition is significantly less effective than normal. Offset inhibition is also reduced in GEPR IC neurons, which leads to a greater than normal incidence of offset (afterdischarge) responses at high stimulus intensities. At AGS onset most IC neurons exhibit burst firing and reductions of acoustically evoked neuronal responses. Responsiveness to acoustic stimuli returns following AGS. This change in IC neuronal firing pattern suggests that the network that governs IC neuronal firing has temporarily changed from the auditory system to the network that mediates seizure propagation. GABA is strongly implicated in intensity-induced, binaural, and offset inhibition in IC neurons. The diminished efficacy of these forms of GABA-mediated acoustically evoked inhibition in the GEPR IC extends previous results, showing reduced effectiveness of exogenously applied GABA and benzodiazepine in GEPR IC neurons. This reduced effectiveness of GABA-mediated inhibition along with excess excitant amino acids in GEPR IC, previously reported, appear to be vital neurotransmitter mechanisms, subserving the exaggerated output of IC neurons at high acoustic intensities. This exaggerated IC firing may be instrumental in seizure initiation in this epilepsy model.

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PubMed1991

Effect of norepinephrine depletion on audiogenic-like seizures elicited by microinfusion of an excitant amino acid into the inferior colliculus of normal rats.

Infusions of an excitant amino acid, N-methyl-D-aspartate (NMDA) into the inferior colliculus (IC) render normal rats susceptible to audiogenic seizures (AGS) and/or spontaneous audiogenic-like seizures without tonic components. The excess excitant amino acid in the IC and the anticonvulsant effects of NMDA antagonists in genetically epilepsy-prone rats (GEPRs), along with innate norepinephrine (NE) deficits and anticonvulsant effects of NE agonists in these animals suggest a mutual role of excitant amino acids and NE in regulating AGS in GEPRs. Saline or 6-hydroxydopamine (6-OHDA, 4 micrograms/side in 2 microliters) was infused bilaterally into the locus coeruleus (LC) of normal male rats and guide cannulas were implanted into the IC. Two weeks later, NMDA was infused bilaterally into the IC (0.5 microliters; 10 nmol/side) and 10 min later the rats were subjected to an electric bell (110 db, 60 s) unless preceded by spontaneous tonic seizures. Tonic seizures were not observed in male rats following NMDA infusions in rats with LC infusions of saline. However, a marked increase in the incidence of tonic seizures was observed in the 6-OHDA-treated rats which were markedly depleted of brain NE as determined by HPLC. These findings indicate that a NE deficit greatly enhances the incidence of tonic convulsions and support the hypothesis that an excitant amino acid excess in the GEPR IC may act to initiate AGS, whereas the NE deficit may allow expression of the tonic components of AGS seen in some GEPRs.

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