GABA Withdrawal Research Articles

Revisiting differential control of sympathetic outflow by the rostral ventrolateral medulla.

The rostral ventrolateral medulla (RVLM) is an important brain region involved in both resting and reflex regulation of the sympathetic nervous system. Anatomical evidence suggests that as a bilateral structure, each RVLM innervates sympathetic preganglionic neurons on both sides of the spinal cord. However, the functional importance of ipsilateral versus contralateral projections from the RVLM is lacking. Similarly, during hypotension, the RVLM is believed to rely primarily on withdrawal of tonic gamma aminobutyric acid (GABA) inhibition to increase sympathetic outflow but whether GABA withdrawal mediates increased activity of functionally different sympathetic nerves is unknown. We sought to test the hypothesis that activation of the ipsilateral versus contralateral RVLM produces differential increases in splanchnic versus adrenal sympathetic nerve activities, as representative examples of functionally different sympathetic nerves. We also tested whether GABA withdrawal is responsible for hypotension-induced increases in splanchnic and adrenal sympathetic nerve activity. To test our hypothesis, we measured splanchnic and adrenal sympathetic nerve activity simultaneously in Inactin-anesthetized, male Sprague-Dawley rats during ipsilateral or contralateral glutamatergic activation of the RVLM. We also produced hypotension (sodium nitroprusside, i.v.) before and after bilateral blockade of GABAA receptors in the RVLM (bicuculline, 5mM 90nL). Glutamate (100mM, 30nL) injected into the ipsilateral or contralateral RVLM produced equivalent increases in splanchnic sympathetic nerve activity, but increased adrenal sympathetic nerve activity by more than double with ipsilateral injections versus contralateral injections (p < 0.05; n = 6). In response to hypotension, increases in adrenal sympathetic nerve activity were similar after bicuculline (p > 0.05), but splanchnic sympathetic nerve activity responses were eliminated (p < 0.05; n = 5). These results provide the first functional evidence that the RVLM has predominantly ipsilateral innervation of adrenal nerves. In addition, baroreflex-mediated increases in splanchnic but not adrenal sympathetic nerve activity are mediated by GABAA receptors in the RVLM. Our studies provide a deeper understanding of neural control of sympathetic regulation and insight towards novel treatments for cardiovascular disease involving sympathetic nervous system dysregulation.

Elevated striatal glutamate + glutamine in recreational cannabis users during abstinence

Cannabis withdrawal symptoms contribute to relapse, but the underlying mechanism remains unclear. We hypothesize that cannabis withdrawal may be associated with a reset of regional γ-amino butyric acid (GABA) and glutamate concentrations secondary to changes in the endocannabinoid system during abstinence and conducted a study on this issue. We used magnetic resonance spectroscopy (MRS) to detect the associated changes of these neurochemicals in twenty-six frequent, recreational cannabis users and eleven age-matched non-using controls. Twenty users (8F/12M) and ten control (5F/5M) participants completed a verified 21-day abstinence period. Striatal GABA and glutamine concentrations were measured at baseline and on abstinence days 7 and 21 in conjunction with measures of cannabis withdrawal symptoms and mood state. Cannabis users reported increased self-reported ratings of cannabis-withdrawal-symptoms on abstinence day 7 relative to controls. Striatal glutamate + glutamine (Glx) group concentrations were elevated in cannabis users at baseline and abstinence days 7 and 21 (F = 7.16, p = 0.012), and changes in GABA concentration and withdrawal symptoms between baseline and abstinence day 7 were positively correlated (r = 0.550, p = 0.010). In addition, baseline striatal GABA concentrations were negatively correlated with withdrawal symptoms on abstinence day 7 (r = −0.680, p = 0.003). Our data demonstrate that striatal Glx was elevated in cannabis users and baseline striatal GABA correlated with withdrawal during the abstinence. In addition, striatal GABA may temporally correlate with self-reported withdrawal symptoms during the initial days of abrupt cannabis abstinence. These findings provide preliminary evidence that striatal GABA and Glx are associated with the severity of cannabis withdrawal.

GABA Levels in The Dorsal Anterior Cingulate Cortex Associated with Difficulty Ignoring Smoking-Related Cues in Tobacco-Dependent Volunteers

Substance abusers have difficulty ignoring drug-related cues, which is associated with relapse vulnerability. This 'attentional bias' towards drug cues translates into an inability to ignore drug-related stimuli and may reflect deficits in the brain regions, such as the dorsal anterior cingulate cortex (dACC)-a key region in cognitive control and adaptive decision making. Quantifying relationships between attentional biases to drug cues and dACC neurochemistry could aid in identifying neurobiological mechanisms associated with increased relapse vulnerability precipitated by drug cues. As gamma-aminobutyric acid (GABA) deficits have been linked to impaired cognition and addictive disorders, we hypothesized that reduced GABA in the dACC would be associated with increased attentional biases towards smoking-related cues. We confirmed this hypothesis among nicotine-dependent tobacco smokers by combining an offline behavioral measure of attentional bias with magnetic resonance spectroscopy. Smokers with the greatest attentional bias also experienced more negative affect during early nicotine withdrawal. Findings revealed a relationship between heightened reactivity to drug cues, and both decreasing dACC GABA and early withdrawal symptoms. Because reduced GABA function in frontal brain regions disrupt cognitive function, our findings suggest that smokers with diminished dACC GABA may lack the cognitive resources to successfully ignore highly salient distractors such as tobacco-related stimuli and therefore might be more prone to cue-induced relapse. This newly discovered relationship between dACC GABA and attentional bias provides evidence for a neurochemical target, which may aid smoking cessation in highly cue-reactive individuals.

Loss of phase synchrony in an animal model of partial status epilepticus

Interrupting a focal, chronic infusion of GABA to the rat motor cortex initiates the progressive emergence of a sustained spiking electroencephalographic (EEG) activity, associated with myoclonic jerks of the corresponding body territory. This activity is maintained over several hours, has an average frequency of 1.5 Hz, is localized to the infusion site and never generalizes. The GABA withdrawal syndrome (GWS) has therefore features of partial status epilepticus. Changes in EEG signals associated with the GWS were studied in freely moving rats by measuring the phase synchrony between bilateral epidural records from the neocortex. Our results showed (i) epileptic activity was associated with a striking decrease in phase synchrony between all pairs of electrodes including the focus, predominantly in the 1–6 Hz frequency range. There was a mean decrease of 75.34±5.26% in phase synchrony levels between the period before GABA interruption and the period after epileptic activity appeared. (ii) This reduction in synchrony contrasted with an increase of power spectral density in the corresponding EEG channels over the same 1–6 Hz frequency range, (iii) neither changes in synchrony nor in nonlinear dynamics were detected before the first EEG spikes, (iv) systemic injection of ketamine, an antagonist of N-methyl-d-aspartic acid (NMDA) receptors, modified transiently both epileptic activity and the synchrony profile. (v) Spiking activity and synchrony changes were suppressed by reperfusion of GABA. Our data suggest that, during a partial status epilepticus, interactions between the epileptic focus and connected neocortical neuronal populations are dramatically decreased in low frequencies.

Exaggeration of epileptic-like patterns by nicotine receptor activation during the GABA withdrawal syndrome

To understand how nicotinic cholinergic receptors may participate in epileptic seizures, we tested the effects of nicotine and of the competitive nicotinic antagonists dihydro-β-erythroidine and α-bungarotoxin on synaptic paroxysmal depolarization shifts (PDSs) and intrinsic bursts of action potentials recorded in slices from rats presenting a cortical status epilepticus. This model named GABA-withdrawal syndrome (GWS) appears consecutive to the interruption of a prolonged intracortical GABA infusion. Effects of both nicotinic antagonists suggest a distinct involvement of α4-β2 and α7 subunits in shaping individual PDSs and patterning repetitive bursts. On one hand, in GWS rats, an increase of PDS latency and prolongation of PDS and bursts were induced by nicotine and reduced by dihydro-β-erythroidine, but not by α-bungarotoxin. The K + blocker tetraethylammonium also increased duration without changing latency. Thus, dihydro-β-erythroidine-sensitive receptors exert distinct controls on the presynaptic generation of PDS and on the process which terminates PDSs and bursts. On the other hand, α-bungarotoxin depolarized neurons and generated rhythmic discharges of clustered bursts. Clustered bursts were also observed in slices obtained from GWS rats treated with the acetylcholinesterase inhibitor eserine. We suggest that both dihydro-β-erythroidine and α-bungarotoxin-sensitive sites control paroxysmic activities in GWS and could be involved in some human and animal epilepsies presenting mutations of nicotinic cholinergic receptors.

Hyperexcitability induced by GABA withdrawal facilitates hippocampal long-term potentiation

In some mammals, epileptic seizures have been induced in the cerebral cortex, hippocampus and other limbic structures after the sudden suppression of chronically infused GABA. This hyperexcitability state induced by the endogenous neurotransmitter resembles the withdrawal seizure-responses to other GABA A receptor agonists such as benzodiazepines, barbiturates and alcohol. Hyperexcitability induced by GABA withdrawal also persists in in vitro preparation. Hippocampal slices, obtained from rats with seizures induced by GABA-withdrawal showed field potential oscillations and paroxysmal activity in the Ammon's horn region 1. During GABA-withdrawal hyperexcitability the threshold of hippocampal long-term potentiation (LTP) decreased to a point in which a brief frequency stimulation that normally failed to produce long lasting changes in synaptic strength, was now able to induce LTP. Facilitation of the LTP induction was associated with a decreased GABA A-mediated inhibitory activity, because the effect of the GABA A receptor antagonist, bicuculline, was occluded during hyperexcitability and the dose-response curve for bicuculline showed a 50% efficacy reduction with a shift in the effective concentration required for half-maximal activation from 4.5–1.1 μM relative to controls. Nevertheless, the dissociation constant of the antagonist did not change significantly. Our results support the idea that changes in hippocampal plasticity under altered inhibitory neurotransmission states, like those induced by withdrawal syndromes to anxiolytic, sedative or anticonvulsant drugs may be engaged during seizures.

Hyperexcitability induced by GABA withdrawal facilitates hippocampal long-term potentiation

Hyperexcitability induced by GABA withdrawal facilitates hippocampal long-term potentiation

Hippocampal hyperexcitability induced by GABA withdrawal is due to down-regulation of GABA A receptors

The sudden interruption of an intracortical instillation of exogenous γ-aminobutyric acid (GABA) generates an epileptic focus in mammals. Seizures elicited by GABA withdrawal (GW) last for weeks. A similar withdrawal-induced hyperexcitability is also produced by several GABA A receptor agonists. This work reports a quantitative analysis of GW-induced hyperexcitability produced in the hippocampus in vitro. GW produced a left-ward displacement of the input/output (I/O) function, suggesting that the postsynaptic component is predominant to explain the hyperexcitability. A decrease in the inhibitory efficacy of the GABA A receptor agonist, muscimol, confirmed that inhibition was impaired. Binding saturation experiments demonstrated a decrease in [ 3H]-muscimol binding after GABA withdrawal showing a close correlation with the development of hyperexcitability. All these modifications coursed without changes in receptor affinity ( K D) for muscimol or bicuculline as demonstrated by both binding studies and Schild analysis. It is concluded that, in the CA1 region of the hippocampus, it is the number of functional GABA A receptors, and not the affinity of the receptor, what is decreased during GW-induced hyperexcitability.

Audiogenic Seizure Susceptibility Is Induced by Termination of Continuous Infusion of γ-Aminobutyric Acid or an N-Methyl-[formula omitted]-aspartic Acid Antagonist into the Inferior Colliculus

The inferior colliculus (IC) is strongly implicated in seizure initiation in a genetic form of audiogenic seizures (AGS) and in AGS observed during ethanol withdrawal (ETX). Ethanol is known to block the actions of excitatory amino acids (EAA) and enhance the actions of γ-aminobutyric acid (GABA) in several brain areas, including the IC. The present study investigated the effects on susceptibility to AGS following withdrawal from continuous blockade of N-methyl-d-aspartic acid (NMDA) receptors or continuous activation of GABA receptors in the IC. This involved infusion of GABA (1 M) or a competitive NMDA antagonist, dl-2-amino-7-phosphonoheptanoic acid (AP7, 1 mM), at 0.25 μl/h for 7 days using an Alzet osmotic minipump. Following abrupt termination of the infusion, AGS susceptibility began at 30 min. The incidence of AGS was 38.9 and 56.3% following GABA and AP7 withdrawal, respectively. The AGS behaviors observed during withdrawal, which included wild running and bouncing clonus, were very similar to those evoked by acoustic stimuli during ETX. AGS susceptibility lasted for several hours and in 13% of animals persisted for up to 6 months. The current results support diminished GABAergic and elevated glutamatergic function in the IC as the critical mechanisms and sites for AGS initiation. The present study, coupled with previous evidence that chronic ethanol exposure reduced GABA-mediated inhibition and enhanced EAA-mediated excitation, suggests that these amino acid receptor-mediated alterations in the IC are key elements in initiating AGS during ethanol withdrawal.

Muscarinic depression of synaptic transmission in the epileptogenic GABA withdrawal syndrome focus.

The GABA withdrawal syndrome (GWS) is a model of local status epilepticus consecutive to the interruption of a prolonged GABA infusion into the rat somatomotor cortex. Bursting patterns in slices from GWS rats include intrinsic bursts of action potentials (APs) induced by intracellular depolarizing current injection and/or paroxysmal depolarization shifts (PDSs) induced by white matter stimulation. Possible changes in the effects of cholinergic drugs after in vivo induction of GWS were investigated on bursting cells (n = 30) intracellularly recorded in neocortical slices. In GWS slices, acetylcholine (Ach, 200-1000 microM) or carbachol (Cch, 50 microM) applications increased the number of bursts induced by depolarizing current injection while synaptically induced PDSs were significantly diminished (by 50-60%) or even blocked independently of the cholinergic-induced depolarization. The intrinsic burst facilitation and PDS depression provoked by Ach or Cch were mimicked by methyl-acetylcholine (mAch, 100-400 microM, n = 11), were reversed by atropine application (1-50 microM, n = 3), and were not mimicked by nicotine (50-100 microM, n = 4), indicating the involvement of muscarinic receptors. In contrast, in nonbursting cells from the same epileptic area (n = 42) or from equivalent area in control rats (n = 24), a nonsignificant muscarinic depression of EPSPs was induced by Cch and Ach. The mAch depression of excitatory postsynaptic potential (EPSPs) was significantly lower than that seen for PDSs in GWS rats. None of the cholinergic agonists caused bursting appearance in these cells. Therefore the present study demonstrates a unique implication of muscarinic receptors in exerting opposite effects on intrinsic membrane properties and on synaptic transmission in epileptiform GWS. Muscarinic receptor mechanisms may therefore have a protective role against the development and spread of epileptiform activity from the otherwise-activated epileptic focus.

Neocortical hyperexcitability after GABA withdrawal in vitro

The sharp interruption of the intracortical instillation of exogenous γ-aminobutyric acid (GABA), generates an epileptic focus in mammals. Seizures elicited by GABA withdrawal last several days or weeks. The present work reports that GABA withdrawal-induced hyperexcitability can be produced in vitro: a sudden withdrawal of GABA (5 mM; 120 min) or benzodiazepine (60 μM flunitrazepam) from the superfusion, induced a gradual increase in the amplitude of the evoked population spike (PS) recorded on neocortical slices. PS enhancement reached 150% above the control value 2.5 h after GABA withdrawal. GABA withdrawal-induced hyperexcitability was facilitated by progesterone. PS enhancement induced by GABA withdrawal was associated with an impairment of GABA transmission occurring before epileptiform discharges were fully established. Paired pulse inhibition and evoked [ 3H]-GABA release appear decreased; suggesting that cortical hyperexcitability as a result of GABA withdrawal involves pre-synaptic changes. Specific muscimol binding decreased during GABA superfusion but recovered after GABA withdrawal. However, the sensitivity of the post-synaptic response to 3α-OH-5α-pregnan-20-one or allopregnanolone (alloP) was enhanced after GABA withdrawal, suggesting a functional change in the GABA A receptors. The changes described may be the cellular correlates of the withdrawal syndromes appearing after interruption of the administration of GABA A receptor agonists.

GABA withdrawal modifies network activity in cultured hippocampal neurons.

Dissociated hippocampal neurons, grown in culture for 2 to 3 weeks, tended to fire bursts of synaptic currents at fairly regular intervals, representing network activity. A brief exposure of cultured neurons to GABA caused a total suppression of the spontaneous network activity. Following a washout of GABA, the activity was no longer clustered in bursts and instead, the cells fired at a high rate tonic manner. The effect of removing GABA could be seen as long as 1 to 2 days after GABA withdrawal and is expressed as an increase in the number of active cells in a network, as well as in their firing rates. Such striking effects of GABA removal may underlie part of the GABA withdrawal syndrome seen elsewhere.

The short-acting anesthetic propofol produces biphasic effects—depression and withdrawal rebound overshoot—on some (but not all) limbic evoked potentials in the behaving rat

Propofol, the relatively new, short-acting general anesthetic, markedly enhances the action of GABA at the GABA A receptor. To evaluate its effects on field potentials evoked in the dentate gyrus (DG) during the anesthetic and recovery periods, propofol was administered intraperitoneally to behaving rats bearing stimulating electrodes in the dorsal perforant path (DPP), where medial perforant path fibers predominate, and in the anterior piriform cortex (PC; i.e., olfactory cortex), and recording electrodes in the DG. Input from the PC reaches the DG via the lateral perforant path. Population slow waves (SWs) were evoked by paired-pulse stimulation of the PC at a 32 ms interstimulus interval (ISI) to produce paired-pulse facilitation in the awake animal. We had previously demonstrated that amplitude of SW2 (produced by the second stimulus) was greatly decreased by GABAergic drugs and increased by antiGABAergic convulsant agents. After administration of propofol, mean amplitude of SW2 decreased immediately and remained low for 30–60 min during propofol-induced sleep (as expected), then unexpectedly increased to about 1.5- to 2-fold above pretreatment levels at 2–4 h before gradually returning to pretreatment levels. In addition, the DPP was stimulated to produce either paired-pulse inhibition (20 ms ISI) or facilitation (32 ms ISI) of DG population spikes (PSs) in the awake animal. PS2 was much more inhibited during propofol-induced sleep, than during the pretreatment period, consistent with an expected marked increase in recurrent inhibition. An overshoot in PS2 amplitude was observed only occasionally during recovery, suggesting that withdrawal overshoot in amplitudes is more characteristic of PC-evoked DG SW2 potentials. The overshoot in SW2 amplitude during recovery may have been related to propofol's `rapid on–rapid off' actions on the GABA A receptor, perhaps resulting in a phenomenon like the `GABA withdrawal syndrome'. Such an effect, if true, may help explain the rare occurrence of seizures, especially during recovery, associated with its use clinically.

Ethanol, GABA and Epilepsy

Ethanol exerts its behavioral effects largely by interacting with receptors to brain neurotransmitters. The molecular mechanisms involving these interactions are still not well known since an ideal model for their study is currently unavailable. In addition, responses to alcohol may vary due to factors such as genetic predisposition, ethanol concentration consumed, and stimuli such as stress, socialization, etc. The chronic consumption of alcohol, similar to that of other drugs such as benzodiazepines and barbiturates, is linked to GABAergic neurotransmission. GABA is the predominant inhibitory neurotransmitter in the brain. In a context of substance abuse, these three drugs first cause a gratifying effect, later tolerance and finally, physical and psychological dependence. If consumption is interrupted abruptly, a withdrawal syndrome occurs. The Alcohol Withdrawal Syndrome (AWS) is a state of hyperexcitability characterized by anxiety, fear, muscular rigidity and tonic-clonic seizures with epileptiform-type characteristics. The epileptic seizures seen during AWS are often similar to those seen in experimental epilepsy models such as “kindling” or GABA Withdrawal Syndrome (GWS) models. A possible correlation between these models and AWS will allow for a better understanding of the cellular and molecular effects that alcohol exerts on the brain.

Nicotinic and muscarinic modulation of epileptic activities in the rat GABA withdrawal syndrome

Nicotinic and muscarinic modulation of epileptic activities in the rat GABA withdrawal syndrome

A potassium current controls burst termination in rat neocortical neurons after GABA withdrawal

Bursting activities were investigated under conditions of reduced outward K + currents in neocortical slices obtained from rats presenting the γ-aminobutyric acid (GABA)-withdrawal syndrome (GWS), a focal epilepsy consecutive to the interruption of a chronic intracortical GABA infusion into the somatomotor cortex. These bursts were induced by intracellular depolarizing current injection and/or by white matter stimulation. Tetraethylammonium (TEA) at doses which did not change input resistance, spike duration or first interspike time interval abolished the burst terminating process and induced plateau-like potentials (up to 500 ms) which were tetrodotoxin-resistant and blocked by Ca 2+ antagonists Cd 2+ and Co 2+. Therefore, it appears that bursts during GWS are generated by Ca 2+-dependent plateau potentials which are terminated by a K + current highly sensitive to TEA.

High expression of noradrenaline, choline acetyltransferase and glial fibrillary acidic protein in the epileptic focus consecutive to GABA withdrawal. An immunocytochemical study

Interruption of a chronic GABA infusion into the rat somatosensory cortex induces the appearance of focal epileptic manifestations, known as the ‘GABA withdrawal syndrome’ (GWS). The aim of the present study was to determine, by immunocytochemistry, if neurotransmitters other than GABA are involved in GWS, namely: noradrenaline (NA), serotonin, choline acetyltransferase (CAT), cholecystokinin, neuropeptide Y, somatostatin and glial fibrillary acid protein (GFAP). Immunocytochemical data were compared in three animal groups: GABA-, saline- and L-aspartate ( L-Asp)-infused rats. Only GABA-infused rats presented epileptic manifestations after interruption of the infusion. Saline- and L-Asp-infused rats served as controls. Observations were limited to the region surrounding the cortical infusion site. GABA-infused rats showed in the zone of the epileptic focus a number of cell bodies strongly immunoreactive to NA antibodies much larger than control rats. In addition, NA-immunoreactive fibers formed a dense plexus and some of them were observed around perikarya. In saline- and L-Asp-infused rats, the NA-immunolabelled fibers were sparse and NA immunolabelling was rarely observed in cell bodies. These results contrast to those obtained for the serotonergic system, where no significant difference was observed among the three groups of rats. CAT immunolabelling was observed in cell bodies, but not in nerve terminals in rats of the three groups. The number of CAT-immunoreactive cell bodies was much greater in GABA-infused rats than in the control animals. GFAP immunolabelling showed an important number of astrocytes throughout the cortex of the GABA-infused hemisphere, whereas, astrocytic reaction was limited to the infusion site in controls. Immunocytochemical data concerning peptides revealed cortical neuronal elements labelled similarly in the three groups of rats. Noradrenergic, cholinergic and glial modifications observed mainly in GABA-infused rats can result from lesion and from a specific action of GABA in chronic infusion. These modifications may contribute to the epileptogenesis of GWS, as recently demonstrated by electrophysiological recordings that show a modulating action of NA on firing activity of neurons involved in the epileptic focus.

Noradrenaline mediates paradoxical effects on rat neocortical neurons after GABA withdrawal

1. The aim of the present study was to determine the role of noradrenergic neurotransmission in neuronal activities intracellularly recorded in neocortical slices obtained from rats presenting the gamma-aminobutyric acid (GABA) withdrawal syndrome (GWS), a focal epilepsy consecutive to the interruption of a chronic intracortical GABA infusion into the somatomotor cortex. Neurons recorded in the epileptic focus area (n = 52) were bursting or nonbursting cells. Intrinsic bursting (IB, n = 20) cells presented bursts of action potentials (APs) to an intracellular depolarizing current injection and paroxysmal depolarization shifts (PDSs) to white matter stimulation. Synaptic bursting (SB, n = 22) cells presented only PDSs. Nonbursting (NB, n = 10) cells presented no burst after either synaptic stimulation or depolarizing current injection. Results were compared with those obtained from NB neurons (n = 4) recorded in slices from saline-infused rats. 2. In all of the recorded neurons, bath application of norepinephrine (NE, 10 and 100 microM) provoked a depolarization (1-5 mV) associated with a decrease in input K+ conductance having a mean reversal potential at -90 to -102 mV, not significantly different for bursting and nonbursting cells. This reversal potential differed from that of Cl(-)-mediated inhibitory postsynaptic potentials (-70 mV) elicited in NB cells by electrical stimulation of the white matter. 3. In IB cells, the NE-induced depolarization replaced the intrinsic bursts by a sustained repetitive discharge of single APs and caused intrinsic bursts to appear during previously subthreshold depolarizing current pulses. These NE-increased activities were abolished by dihydropyridine nitrendipine (1 microM) and by Cd2+ (0.5 mM) or Co2+ (2 mM), thus confirming that Ca2+ currents contribute to burst generation in IB cells. 4. In both NB and SB cells recorded in slices from GWS rats, NE provoked the appearance of intrinsic bursts of APs during steps of depolarizing current injections. In addition, in NB cells, NE caused synaptic bursts to appear after white matter stimulation. These NE-induced bursts were dihydropyridine (nitrendipine, 1 microM)- and Cd2+ (0.5 mM)- or Co2+ (2 mM)-sensitive and were related to an increased AP-afterdepolarization. The fast AP-afterhyperpolarization was not affected by NE. In NB cells recorded in slices from saline-infused rats (n = 4) NE did not provoke the appearance of bursts even when stimulation intensity was increased up to three times.(ABSTRACT TRUNCATED AT 400 WORDS)

Hyperexcitability of hippocampal CA1 region in brain slices after GABA withdrawal

The interruption of GABA infusion in the cerebral cortex and in the hippocampus produces electrographic seizures in rats. Here, we have used the hippocampal slice preparation to induce a ‘GABA withdrawal syndrome (GWS)’. With the stimulation parameters used (0.2 Hz, 200 μs), activation of the Schaffer afferents produced one population spike in the CA1 subfield, while multiple population spikes were observed in the slices previously incubated in GABA. Also, we recorded an increase in the amplitude of the population spike when compared to its control value. Paired pulse test showed absence of recurrent inhibition in these slices. These results suggest a dysfunction in GABAergic neurotransmission.

Effects of 3-hydroxy,3-ethyl,3-phenylpropionamide (HEPP) on rat models of generalized and focal epilepsy

The GABA withdrawal syndrome (GWS) is a new model of focal epilepsy in which paroxysmal activity is induced through the interruption of a chronic, intracortical infusion of GABA. Preliminary studies have shown extraordinary resistance of this epileptogenic activity to classic anticonvulsants including diazepam, the most effective agent for treating status epilepticus. However, GWS can be inhibited by GABA itself. The rat with petit mal-like seizures is a genetic model of generalized non-convulsive epilepsy (GNCE), with behavioral characteristics and electrical (spike-and-wave discharges) signs resembling absences. Moreover, GABAmimetics aggravate this type of seizure. Rats with GWS induced by cessation of a localized GABA infusion (50 μg/μ1/h for 24 h), and the rat model of GNCE, were treated with HEPP, a new anticonvulsant agent. In the case of GWS, the drug produced a significant decrease of focal spike activity in animals which started discharging at low frequencies while in rats with higher frequency discharge, HEPP was without effect. HEPP administered on the second day of the GWS in naive rats had no effect. In rats with GNCE, doses of 50 and 100 mg/kg i.p. blocked the spike-and-wave discharges. The higher dose produced sedation in this absence seizures model. Although the mechanism of action of HEPP is still unknown, its unique antiepileptic profile deserves further studies.