A1 adenosine receptor-mediated block of epileptiform activity induced in zero magnesium in rat neocortex in vitro

It has been suggested that endogenous chemical substances such as adenosine, released during a seizure attack, may act as anticonvulsants in vivo. To further investigate this putative role, we have tested adenosine and stable adenosine analogues for anticonvulsant activity in vitro against ictal-like epileptiform activity induced by the removal of magnesium ions from medium superfusing wedges and slices of rat neocortex. Purinoceptor agonists attenuated such burst activity with a potency profile of L-phenylisopropyl-adenosine greater than 2-chloroadenosine greater than adenosine, suggesting that their anticonvulsant actions were mediated via the A1 adenosine receptor sub-type. Adenosine exerted no apparent effect on responses to agonists acting at glutamate receptor sub-types, implying no direct postsynaptic activity at glutamatergic synapses. Adenosine receptor antagonists, the methylxanthines (3-isobutyl-1-methylxanthine greater than theophylline) markedly enhanced established epileptiform activity and reversed the anticonvulsant action of adenosine. The selectivity of this reversal was demonstrated by the lack of effect of methylxanthines on pentobarbitone-induced inhibitions of epileptiform bursts. When added to a normal medium containing 1 mM magnesium, the methylxanthines were unable to induce long-lasting ictal-like epileptiform activity.     

Background potassium concentrations and epileptiform discharges. I. Electrophysiological characteristics of neuronal activity

Intra- and extracellular recording techniques were used to study the epileptiform activity generated by guinea pig hippocampal slices perfused with free-magnesium artificial cerebrospinal fluid in the presence of physiologic (4 mM), reduced (2 mM) or elevated (8 mM) extracellular potassium concentrations ([K(+)](o)). Extracellular field potentials along with intracellular recordings were recorded in CA1 or CA3 region. Reduction of [K(+)](o) significantly increased the latency of epileptiform field potential (EFP) appearance as well as burst discharge duration and decreased EFP repetition rate. Depending on different background [K(+)](o), epileptiform burst discharges appeared in different patterns including varied types of paroxysmal depolarisation shifts and burst activity in CA1 and CA3 subfields. Comparison with physiological and increased [K(+)](o,) reduction of [K(+)](o) significantly increased the mean duration of bursts, mean amplitude of depolarisation, mean after-hyperpolarisation duration, and inter-spike intervals in both CA1 and CA3 areas. Three distinct patterns were distinguished on the basis of their evoked firing pattern in response to application of depolarising current pulses in the interval of epileptiform burst discharges. Neurons superfused with 2 mM [K(+)](o) presented fast adapting pattern while cells washed with 4 or 8 mM [K(+)](o) exhibited intrinsically bursting or slow adapting patterns. Comparing the groups with different background [K(+)](o), there is a more severe form of discharges in low K(+) and a subtle difference between 4 and 8 mM K(+). The data indicate the importance of background [K(+)](o) on epileptiform burst discharge pattern and characteristics.     

Muscarinic Modulation of Intrinsic Burst Firing in Rat Hippocampal Neurons

Intracellular recordings in rat hippocampal slices were used to examine how exogenous and endogenous cholinergic agonists modulate the firing pattern of intrinsically burst-firing pyramidal cells. About 24% of CA1 pyramidal cells generated all-or-none, high-frequency bursts of fast action potentials in response to intracellular injection of long positive current pulses. Application of carbachol (5 μM) converted burst firing in these neurons into regular trains of independent spikes. Acetylcholine (5 μM) exerted a similar effect, provided acetylcholine esterase activity was blocked with neostigmine (2 μM). Atropine (1 μM) reversed this cholinergic effect, indicating its mediation by muscarinic receptors. Cholinergic agonists also caused mild neuronal depolarization but the block of intrinsic burst firing was independent of this effect. Repetitive stimulation of cholinergic fibres in the presence of neostigmine (2 μM) evoked a slow cholinergic excitatory postsynaptic potential (EPSP) lasting about a minute. During the slow EPSP, burst firing could not be evoked by depolarizing pulses and the neurons fired in regular mode. These effects were prevented by pretreatment with atropine (1 μM). Exogenously applied cholinergic agonists and endogenously released acetylcholine also reduced spike frequency accommodation and suppressed the long-duration afterhyperpolarization in burst-firing pyramidal cells in an atropine-sensitive manner. A membrane-permeable cAMP analogue (8-bromo-cAMP; 1 mM) also reduced frequency accommodation and blocked the long-duration afterhyperpolarization, but did not affect intrinsic burst firing at all. Taken together, the data show that muscarinic receptor stimulation transforms the stereotyped, phasic response of burst-firing neurons into stimulus-graded, tonic discharge.     

Synchronization of GABAergic interneuronal networks during seizure-like activity in the rat horizontal hippocampal slice

We studied the contribution of GABAergic (gamma-aminobutyric acid) neurotransmission to epileptiform activity using the horizontal hippocampal rat brain slice. Seizure-like (ictal) activity was evoked in the CA1 area by applying high-frequency trains (80 Hz for 2 s) to the Schaffer collaterals. Whole-cell recordings from stratum oriens-alveus interneurons revealed burst firing with superimposed high-frequency spiking which was synchronous with field events and pyramidal cell firing during ictal activity. On the other hand, interictal interneuronal bursts were synchronous with large-amplitude inhibitory postsynaptic potentials (IPSPs) in pyramidal cells. Excitatory and inhibitory postsynaptic potentials were simultaneously received by pyramidal neurons during the ictal afterdischarge, and were synchronous with interneuronal bursting and field potential ictal events. The GABAA receptor antagonist bicuculline greatly reduced the duration of the ictal activity in the CA1 layer, and evoked rhythmic interictal synchronous bursting of interneurons and pyramidal cells. With intact GABAergic transmission, interictal field potential events were synchronous with large amplitude IPSPs (9.8 +/- 2.4 mV) in CA1 pyramidal cells, and with interneuronal bursting. Simultaneous dual recordings revealed synchronous IPSPs received by widely separated pyramidal neurons during ictal and interictal periods, indicative of widespread interneuronal firing synchrony throughout the hippocampus. CA3 pyramidal neurons fired in synchrony with interictal field potential events recorded in the CA1 layer, and glutamate receptor antagonists abolished interictal interneuronal firing and synchronous large amplitude IPSPs received by CA1 pyramidal cells. These observations provide evidence that the interneuronal network may be entrained in hyperexcitable states by GABAergic and glutamatergic mechanisms.     

Glucose regulation of synaptic transmission in the dorsolateral septal nucleus of the rat.

Intracellular recordings were made from neurons in the dorsolateral septal nucleus (DLSN) of rat brain slices. Lowering the concentration of extracellular glucose resulted in a concentration-dependent membrane hyperpolarization associated with a cessation of spontaneous firing. The amplitude of the excitatory postsynaptic potential (EPSP), inhibitory postsynaptic potential (IPSP), and late hyperpolarizing potential (LHP) evoked by a single stimulus applied to the fimbrial/fornix pathway was decreased when the concentration of glucose was reduced to 0-2 mM. Substitution of glucose with 2-deoxy-D-glucose (11 mM), an antimetabolite of glucose substrate, mimicked the effects of glucose depletion. Mannoheptulose (10-20 mM), a potent hexokinase blocker, and dinitrophenol (50 microM), a potent inhibitor of oxidative phosphorylation, produced both the hyperpolarization and inhibition of postsynaptic potentials, even in the presence of 11 mM glucose. The sulphonylureas, glibenclamide (10 microM) and tolbutamide (1 mM), did not antagonize the hyperpolarization and the inhibition of the postsynaptic potentials produced by glucose depletion. The amplitude of membrane depolarizations produced by pressure application of glutamate (10 mM) and the membrane hyperpolarizations produced by pressure application of either muscimol (1 mM) or baclofen (1 mM) were almost unchanged, even when glucose was reduced to 1-2 mM. These results indicate that intracellular glucose metabolism regulates the function of septal neurons, not only by changing the resting membrane potential, but also by presynaptically affecting neurotransmission between the hippocampal formation and the lateral septum.     

Synaptic responses of neurons of the nucleus tractus solitarius in vitro

Postsynaptic responses of neurons in the nucleus tractus solitarius (NTS) have been studied in an in vitro slice preparation using extra- and intracellular recording. Single or paired pulse stimulations were delivered to afferent fibers within the tractus solitarius (TS) to activate orthodromic responses in these neurons. Most NTS neurons displayed an initial synaptic excitation followed by inhibition of spontaneous or evoked firing lasting up to 150-200 ms after stimulation. Excitatory postsynaptic potentials (EPSPs), recorded intracellularly, were increased in amplitude by membrane hyperpolarization. Large afterhyperpolarizations followed action potentials triggered by the EPSPs or evoked by intracellular current injections. Intracellular evidence for synaptic inhibition within the NTS included: (1) the presence, after Cl-injection, of flurries of spontaneous PSPs likely to be inverted inhibitory postsynaptic potentials; (2) reduction of the size of a test EPSP by a previous subthreshold TS conditioning volley; and (3) hyperpolarizing PSPs recorded in some neurons. Other NTS neurons exhibited prolonged excitatory responses to TS stimulation and could be local inhibitory interneurons. These results may help specify synaptic mechanisms in the NTS that could play an integrative role in the relay of visceral sensory inputs to higher order effectors.     

Ketamine suppresses synchronized discharges in the disinhibited amygdala slice.

The effect of ketamine on the paroxysmal depolarizing shift (PDS) induced by bicuculline was studied in rat amygdala slices using intracellular recording techniques. Stimulation of the ventral endopyriform nucleus evoked an excitatory postsynaptic potential (EPSP). After exposure to bicuculline (20 microM), the same stimulus intensity evoked burst firing. Superfusion of ketamine reversibly reduced the duration of PDS. Pretreatment of amygdala slices with DL-2-amino-5-phosphonovaleate (DL-APV, 50 microM) occluded the effect of ketamine suggesting that ketamine shortened the burst duration via its blocking action on the NMDA receptors. In all neurons tested, a large depolarizing shift remained in the presence of ketamine. The ketamine-resistant component was blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 8 microM) indicating its mediation by the non-NMDA receptors.     

The effect of barium and some channel blockers on sensory discharge of the frog labyrinth posterior canal recorded at rest and during rotation

The effect on the afferent synaptic transmission of Ba2+, Sr2+, tetraethylammonium (TEA) and 4-aminopyridine (4-AP) has been investigated in the isolated frog labyrinth by intracellularly recording the posterior canal resting and evoked receptor discharge. BaCl2 (0.3 mM) or SrCl2 (1.8 mM) substitution for normal external CaCl2 restored the afferent activity without affecting the membrane potential of the sensory fibres. On further increasing Ba2+ concentration (0.5-5 mM) a dose-dependent increase in the EPSP and spike discharges was observed in all the units examined. Ba2+ (1.8-4 mM) removed the depression of the sensory activity operated by CoCl2 (3 mM), while its facilitatory effect was completely antagonized by raising Ca2+ concentration (up to 10 mM). TEA (20 mM) elicited a clear-cut increase in the EPSP and spike discharges which, however, was less consistent than that produced by Ba2+ (1 mM). The increment in spike frequency produced by TEA and Ba2+ proved to be inversely related to the initial resting firing level of the different units. The 4-AP (4-20 mM) effect resulted in a decrease of the sensory activity, which was fully restored by TEA or Ba2+. In normal saline a linear relationship was found between the mean unit resting discharge and the respective excitatory peak response during sinusoidal rotation (0.1-0.3 Hz). This result suggest that the mechanical response is mainly determined by the unit resting level. Consistent evoked responses were obtained under TEA and Ba2+ treatment which proved to depend linearly on the new mean resting discharge of the different units. Conversely, a reduced evoked response was invariably observed in all the fibres tested in the presence of 4-AP. The present results suggest that Ba2+ and Sr2+ may substitute for Ca2+ in the transmitter release process at the cyto-neural junction, the ability of Ba2+ being even larger than that of Sr2+ and Ca2+ itself. The effects of TEA and 4-AP are discussed in the light of their possible interaction with the presynaptic K+-currents recently described in hair cells.     

Cesium Potentiates Epileptiform Activities Induced by Bicuculline Methiodide in Rat Neocortex Maintained In Vitro

We report that extracellular application of cesium (Cs+, 3 mM) potentiated the epileptiform discharge evoked by GABAA-receptor antagonist bicuculline methiodide (BMI 50 microM) in rat neocortical slices maintained in vitro. Cs+ changed BMI-induced epileptiform burst of a few hundred milliseconds evoked by extracellular focal stimuli into epileptiform discharge only a few seconds long (1.8-7 s). Moreover, Cs+ induced the appearance of spontaneously occurring epileptiform activities (0.038-0.15 Hz). Simultaneous intracellular/extracellular recordings indicated that each intracellular epileptiform burst was correlated with a field discharge. Variation of the membrane potential modified only the amplitude of the epileptiform burst and did not alter its frequency of occurrence, indicating that each discharge was a synchronous population event. The epileptiform discharges were not blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP 5-10 microM). In contrast, the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX 0.5-5 microM) greatly reduced the duration of each epileptiform discharge by abolishing its afterdischarges in a concentration-dependent manner. This reduction in duration was accompanied by an increase in frequency of occurrence, however. After blockade of non-NMDA receptors with CNQX, a CPP-sensitive spontaneous discharge could be observed. These findings indicate that the inorganic cation Cs+ applied extracellularly can induce spontaneously occurring epileptiform activities in BMI-treated neocortical slices. In addition, receptors of excitatory amino acids play a major role in synchronizing this type of Cs+/BMI-induced spontaneous epileptiform activities.     

Electrophysiology of dissociated hippocampal cultures from fetal mice

Action potentials, postsynaptic potentials (PSPs) and burst potentials have been recorded intracellularly from over 200 neurons in hippocampal cell cultures prepared from fetal mice of 13-18 days gestational age. Repetitively firing action potentials are elicited by intracellular electrical stimulation and often are preceded by stereotyped prepotentials which probably are generated on processes remote from the cell body. In some cells, action potentials are succeeded by long duration depolarizing afterpotentials (0.3--2 sec) with additional superimposed action potentials. Postburst afterhyperpolarization can last up to 2.5 sec. Action potentials are short (0.6--1.2 msec) with peak rates of rise from 64 to 267 V/sec (mean 139 +/- 13 V/sec, 24 cells) and corresponding rates of fall from 21 to 133 V/sec (mean 70 +/- 7 V/sec, 24 cells). Following single action potentials, the afterhyperpolarization is usually less than 10 msec. Inhibitory PSPs occur frequently (up to 70% incidence), have reversal potentials of--30 to--40 mV, and can be evoked in synaptically coupled cell pairs. Excitatory PSPs can initiate prepotentials and action potentials, suggesting dendritic and somatic loci respectively. Neural networks exhibit a broad range of electrophysiologic phenomenology including reciprocal innervation, multiple innervation and synchronous bursting among a widespread population of neurons.     

GABAergic inhibition and epileptiform discharges in the turtle hippocampus in vitro

The effects of excitatory amino acid (EAA) receptor antagonists were examined on intracellularly recorded epileptiform discharges in turtle hippocampal (ventromedial cortical) pyramidal neurons in vitro. Afferent synaptic activation of turtle hippocampal neurons evoked monophasic or biphasic GABAergic inhibitory postsynaptic potentials (IPSPs). In the presence of bicuculline (5 microM) or picrotoxin (100 microM) IPSPs were reduced, and long-lasting ictal-like discharges were transiently observed prior to the establishment of a regular rhythm of discharge of spontaneous paroxysmal depolarization shifts (PDSs). Bicuculline-induced PDSs were reversibly reduced in amplitude and duration, but not abolished by the EAA receptor antagonists kynurenic acid (1 mM), cis-2,3-piperidine dicarboxylic acid (cis-2,3-PDA) (1 mM), or DL-2-amino-5-phosphonovalerate (DL-AP-5) (100 microM), revealing a long-lasting hyperpolarizing afterpotential. These results indicate that the blockade of GABAergic inhibition leads to the genesis of epileptiform discharges, and EAA receptor antagonists (particularly those of the N-methyl-D-aspartate (NMDA) receptor subtype) block the maintained depolarization underlying PDSs, but do not prevent their spontaneous discharge in turtle hippocampus.     

Changes in the postsynaptic responses of spinal cord motor neurons against a background of rhythmic stimulation of the locus coeruleus

Influences of locus coeruleus rhythmical stimulation on the postsynaptic reactions of spinal motoneurons were studied in chloralose anesthetized cats. IPSPs evoked by flexor reflex afferent (FRA) stimulation were inhibited, but EPSPs evoked by FRA and PSPs evoked by low-threshold muscle afferents stimulation were unchanged under these conditions. The inhibition of IPSPs disappeared in reserpine-pretreated animals. Both IPSPs and EPSPs evoked by FRA stimulation were diminished also during rhythmical stimulation of nucleus reticularis pontis oralis. However this effect was not of monoaminergic nature because it was present in reserpine-pretreated animals.     

NMDA receptor antagonists attenuate a portion of the penicillin-induced epileptiform burst

In the CA1 region of the rat hippocampal slice, epileptiform activity was induced by the GABAA antagonist penicillin (PEN, 3.4 mM). The competitive N-methyl-D-aspartate (NMDA) receptor antagonists D-2-amino-7-phosphonoheptanoate (D-AP7) and D-2-amino-5-phosphonovolerate (D-AP5) attenuated extracellularly recorded evoked burst duration, the number of population spikes per evoked bursts and the frequency of spontaneously occurring bursts, but did not affect the sum of the population spike amplitudes or the evoked burst coastline measures due to increases in amplitude of the remaining secondary population spikes. Intracellular recordings showed that many of the secondary action potentials in the PEN burst were decreased in amplitude and broadened in duration, perhaps due to spike inactivation. D-AP7 allowed these secondary action potentials to increase in amplitude, which could explain the increases in secondary population spike amplitude seen extracellularly. Decrements in stimulus strength can mimic the effect of D-AP7 on PEN bursts. These data suggest that there is a portion of the PEN-induced epileptiform burst which is sensitive to NMDA antagonists.     

Chronic exposure to alcohol during development alters the responses to excitatory amino acids in cultured Purkinje neurons.

The effects of chronic alcohol exposure during development on the responses evoked by glutamate and the selective excitatory amino acid receptor agonists quisqualate (Quis) and kainate were studied in cultured cerebellar Purkinje neurons. The cultures were treated with 22 mM or 44 mM ethanol continuously for one or two weeks during the main period of morphological and physiological development. Extracellular recordings used for most studies characterized the responses to all 3 agonists as initial increase in simple spike firing, usually including a period of burst activity, followed by reduced activity or total inhibition, then return to control firing pattern. Analysis of these responses and background spontaneous activity showed several significant differences between control and ethanol treated Purkinje neurons. Background spontaneous firing, agonist evoked firing, the initial period of activity of the response to Quis, and the inhibitory period of the response to glutamate were all significantly reduced in the chronically treated neurons; the inhibitory period of the response to kainate was significantly increased. In contrast to the effects of chronic ethanol exposure, acutely administered ethanol significantly increased background spontaneous firing and the inhibitory period of the response to Quis. Thus, administering both acute and chronic ethanol altered the responses evoked by excitatory amino acids in the developing Purkinje neurons. The effect of chronic ethanol exposure on some response components was similar for all agonists tested and may be linked to changes in intrinsic membrane properties. However, alterations in the inhibitory component of the agonist responses were agonist specific, indicating that receptor-linked actions of ethanol were involved.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibitory effects of N-valproyl-l-tryptophan on high potassium, low calcium and low magnesium-induced CA1 hippocampal epileptiform bursting activity in rat brain slices

N-valproyl-l-tryptophan (VPA-Tryp), new antiepileptic drug, was tested on CA1 hippocampal epileptiform bursting activity obtained by increasing potassium and lowering calcium and magnesium concentrations in the fluid perfusing rat brain slices. Each slice was treated with a single concentration (0.2, 0.5, 1 or 2?mM) of Valproate (VPA) or VPA-Tryp. Both burst duration and interburst frequency during and after treatment were off-line compared with baseline values. For both parameters, the latency and the length of statistically significant response periods as well as the magnitude of drug-induced responses were calculated. VPA-Tryp evoked fewer and weaker early excitatory effects than VPA on bursting activity. On the contrary, VPA-Tryp induced powerful and long-lasting inhibitory effects on epileptiform discharge in a significantly higher number of slices than VPA. In fact, greater length and magnitude of VPA-Tryp-induced inhibition on both interburst frequency and burst duration were observed. Furthermore, VPA-Tryp showed antiepileptic activity at lower concentration than VPA and, when testing both drugs at analogue concentrations, VPA-Tryp evoked responses with either shorter latency or greater effect length and magnitude than VPA.     

Synaptic transmission in the hippocampus: Critical role for glial cells

The importance of glial cells in controlling the neuronal microenvironment has been increasingly recognized. We now demonstrate that glial cells play an integral role in hippocampal synaptic transmission by using the glial-specific metabolic blocker fluoroacetate (FAC) to selectively inhibit glial cell function. FAC inhibits evoked intracellular postsynaptic potentials (PSPs; IC₅₀ = 39 μM) as well as population PSPs (IC₅₀ = 65 μM) in field CA1 of the guinea pig hippocampal slice. Spontaneous synaptic transmission is concurrently decreased. These effects are time and dose dependent. ATP concentrations in glial but not neuronal elements are also significantly reduced with FAC treatment. Simultaneous application of the metabolic substrate isocitrate with FAC prevents both the reduction in glial ATP concentrations and the decrease in evoked PSPs. Given that isocitrate is selectively taken up by glia, these data further support a glial specific metabolic action of FAC. Additionally, FAC has no postsynaptic effects as peak responses to iontophoretically applied glutamate are unchanged. However, the decay of both iontophoretic and evoked PSPs are prolonged following FAC treatment suggesting inhibition of glutamate uptake may contribute to the FAC-induced depression of synaptic potentials. These results show, for the first time, that glial cells are critical for maintenance of synaptic transmission and suggest a role for glial cells in the modulation of synaptic efficacy. © 1994 Wiley-Liss, Inc.     

Topiramate alters excitatory synaptic transmission in mouse hippocampus

Antiepileptic drugs may exert neuroprotective effects by decreasing excessive membrane excitability, neurotransmitter release, or postsynaptic Ca2+ entry. To assess these sites of action, we combined fluorescence Ca2+ imaging with extracellular field recording to analyze axonal excitability, evoked presynaptic Ca2+ entry through presynaptic Ca2+ channels, postsynaptic excitatory field potentials (fEPSP), and postsynaptic Ca2+ buildup ([Capost]) at the mouse hippocampal CA3-CA1 synapse exposed to topiramate (TPM). Topiramate had no effect on presynaptic Ca2+ entry, and produced only a minor inhibition of axonal excitability. Topiramate at concentrations up to 100 microM only slightly reduced the amplitude of the evoked fEPSP, but strongly inhibited the [Capost] evoked by repetitive synaptic activation. Postsynaptically, the action of TPM on the fEPSP and [Capost] was not mediated by an inhibition of the NMDA receptor, or by direct modulation of voltage-dependent Ca2+ channels, but reflected reduced somatic or dendritic membrane depolarization by AMPA and kainate receptors. These results are consistent with the known anticonvulsant properties of TPM. In addition, the ability of TPM to reduce postsynaptic Ca2+ buildup may provide a potential mechanism for neuronal protection during paroxysmal firing associated with epileptic seizures.     

Gamma-aminobutyric acid(B) receptor activation suppresses stimulus-evoked burst firing in rat substantia nigra reticulata neurons

Previous whole-cell patch-pipette studies showed that focal electrical stimulation of the subthalamic nucleus (STN) evokes a long-lasting complex excitatory postsynaptic currents (EPSC) and synaptically evoked bursts of action potentials in substantia nigra pars reticulata (SNR) neurons. Although synaptically evoked bursting may play a role in normal physiology, excessive burst firing correlates with symptoms of Parkinson's disease. We used patch-pipette recordings in rat brain slices to study the effects of baclofen on complex EPSCs and STN-induced burst firing in SNR neurons. Baclofen (1 μM) caused a reversible, 73% reduction in complex EPSCs, and this effect was blocked by the γ-aminobutyric acid(B) antagonist CGP35348 (100 μM). Using the loose-patch method to record extracellular potentials, a lower concentration of baclofen (100 nM) inhibited STN-evoked bursts, while leaving spontaneous firing of action potentials less affected. We suggest that strategies that selectively inhibit burst firing in the SNR might have therapeutic potential in the treatment of Parkinson's disease.     

Ethanol inhibits epileptiform activity and NMDA receptor-mediated Synaptic transmission in rat amygdaloid slices

The effect of ethanol on the epileptiform activity induced by Mg(++)-free solution was studied in rat amygdalar slices using intracellular recording techniques. The spontaneous and evoked epileptiform discharges consisting of an initial burst followed by afterdischarges were observed 20-30 min after switching to Mg(++)-free medium. Superfusion with ethanol (20-100 mM) reversibly reduced the duration of spontaneous and evoked bursting discharges in a concentration-dependent manner. Synaptic response mediated by N-methyl-D-aspartate (NMDA) receptor activation was isolated by application of a solution containing the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and either in Mg(++)-free solution or in the presence of 50 microM bicuculline. Application of ethanol reversibly suppressed the duration of NMDA receptor-mediated synaptic response. These results suggest that intoxicating concentrations of ethanol possess anticonvulsant activity through blocking the NMDA receptor-mediated synaptic excitation. In addition, the observed effect of ethanol on NMDA receptor-mediated synaptic response could be relevant to the cognitive and behavioral manifestations seen in some alcoholics.     

Kindling-induced persistent alterations in the membrane and synaptic properties of CA1 pyramidal neurons.

Intracellular recordings of CA1 pyramidal cells were performed in in vitro hippocampal slices obtained from control and amygdala- or perforant path-kindled rats. Passive membrane properties did not differ between control and kindled cells. Twenty-three percent of kindled cells, however, displayed burst firing with depolarizing current injection, whereas no control cells produced bursts (P less than 0.01). Two different types of voltage-dependent alteration of depolarizing postsynaptic potentials (PSPs) were also evident in kindled cells. The majority (26/29) of these cells showed a smaller increase (type 1, n = 18), or a sudden decrease (type 2, n = 8), in PSP amplitude with passive membrane hyperpolarization when compared to controls (P less than 0.01). The NMDA antagonist D-APV did not markedly alter the overall slope of the PSP/membrane potential function in either 'type 1' or 'type 2' cells, suggesting that neither behavior was due to a change in the activation characteristics of NMDA receptors. The amplitude of IPSPs was smaller in 'type 1' kindled cells (P less than 0.05) than in controls, however, suggesting that the reduced slope of the PSP/membrane function may be accounted for by a change in inhibition.