Marc L. Zeise

Acamprosate (calciumacetylhomotaurinate) decreases postsynaptic potentials in the rat neocortex: possible involvement of excitatory amino acid receptors.

Acamprosate (calciumacetylhomotaurinate) is used therapeutically against relapse in weaned alcoholics. In the present study, the mechanism of action was investigated by making intracellular in vitro and extracellular in vivo recordings from rat neocortical neurons. Acamprosate (0.1-1 mM) added to the perfusion fluid in vitro reduced excitatory and inhibitory postsynaptic potentials and the depolarizing responses evoked by iontophoretic application of the excitatory amino acids, L-glutamate, L-aspartate, L-homocysteate and N-methyl-D-aspartate, but did not alter the responses to gamma-aminobutyric acid. Acamprosate decreased electrical excitability without apparently changing membrane potential, input resistance, afterhyperpolarization, or threshold and amplitude of the action potential. In vivo iontophoretic application of acamprosate reduced the extracellularly recorded unit activity elicited by iontophoretically applied L-glutamate, whereas spontaneous discharges remained unaffected. These data suggest that acamprosate reduces the postsynaptic efficacy of excitatory amino acid neurotransmitters and lowers neuronal excitability in the neocortex of the rat.

VALPROATE SUPPRESSES N-METHYL-D-ASPARTATE-EVOKED, TRANSIENT DEPOLARIZATIONS IN THE RAT NEOCORTEX IN VITRO

Effects of the antiepileptic drug sodium valproate (VPA) were studied on neocortical pyramidal cells (layer II/III) of the rat in vitro by intracellular recording. VPA (0.1-1 mM) in a dose-related manner suppressed the characteristic transient depolarizations induced by N-methyl-D-aspartate (NMDA) applied iontophoretically Higher concentrations of VPA (5-10 mM) also reduced L-glutamate responses. At these concentrations VPA increased the duration of orthodromically evoked inhibitory postsynaptic potentials and reduced repetitive spike firing induced by depolarizing currents. All effects were fully reversible within about 30 min. These results suggest that an essential mode of action for the anticonvulsant VPA is the attenuation of NMDA receptor-mediated excitation.

N‐Methylaspartate‐Evoked Liberation of Taurine and Phosphoethanolamine In Vivo: Site of Release

Abstract: The effect of N‐methyl‐d,l‐aspartic acid (NMA) on extracellular amino acids was studied in the rabbit hippocampus with the brain dialysis technique. Administration of 0.5 or 5 mM NMA caused a concentration‐dependent liberation of taurine and phosphoethanolamine (PEA). Taurine increased by 1,200% and PEA by 2,400% during perfusion with 5 mM NMA whereas most other amino acids rose by 20–100%. The effect of NMA appeared to be receptor‐mediated, as coperfusion with D‐2‐amino‐5‐phosphonovaleric acid curtailed the NMA response by some 90%. The NMA‐stimulated release of taurine and PEA was suppressed when Ca2+ was omitted and further inhibited when Co2+ was included in the perfusion medium. The effect of NMA was mimicked by the endogenous NMA agonist quinolinic acid and the partial NMA agonist d,l‐cis‐2,3‐piperidine dicarboxylic acid. Although the NMA‐evoked release of taurine and PEA was Ca2+‐dependent in vivo, NMA had no effect on Ca2+ accumulation in hippocampal synaptosomes. The previously reported NMA‐induced activation of dendritic Ca2+ spikes and the lack of effect on synaptosomal Ca2+ uptake suggest that taurine and PEA are released from sites other than nerve terminals, possibly from dendrosomatic sites. This notion was strengthened by the absence of an effect of NMA on the efflux of radiolabelled taurine from hippocampal synaptosomes. In contrast, high K+ stimulated synaptosomal uptake of Ca2+ and release of taurine.

Interleukin-1β increases synaptic inhibition in rat hippocampal pyramidal neurons in vitro

Interleukin-1 (IL-1), a cytokine with a broad spectrum of biological activity, modulates electrical properties of central neurons in the brain. The effects of IL-1 beta (143 pM) on conductances opened by synaptic stimulation of the Schaffer collaterals were studied by intracellular recording of hippocampal pyramidal cells of the CA1 region. IL-1 beta enhanced and prolonged synaptic inhibition by about 2 to 3-fold. Heat-inactivated IL-1 beta had no effect. This finding implies that IL-1 beta changes interneuronal communication in the hippocampus with a possible impact on neuronal plasticity.

L-homocysteic acid but not L-glutamate is an endogenous N-methyl-D-aspartic acid receptor preferring agonist in rat neocortical neurons in vitro.

The effects of ionophoretically applied L-homocysteate (L-HCA), L-glutamate (L-Glu) and N-methyl-D-aspartate (NMDA) were compared in rat neocortical neurons recorded intracellularly in vitro. The firing pattern and the time course of membrane depolarization induced by L-HCA resembled those of NMDA responses. Action potentials evoked by NMDA and L-HCA were superimposed upon slow depolarizations in a burst-like pattern, while L-Glu elicited single spike discharges. Ionophoretically applied D-2-amino-5-phosphonovalerate (2-APV) at doses sufficient to abolish NMDA responses, markedly reduced the L-HCA induced depolarizations but had no detectable effect on the L-Glu responses. The present findings are consistent with a possible role of L-HCA as an NMDA receptor preferring neurotransmitter in the rat frontal cortex.

Melatonin lowers excitability of guinea pig hippocampal neurons in vitro

SummaryAction of melatonin (N-acetyl-5-methoxytryptamine; MEL) on guinea pig hippocampal cells (CA3 neurons and dentate granule cells) were studied in vitro using both extra- and intracellular recording. MEL (1–10 mmol/l) had the following effects: 1.Response to repetitive synaptic stimulation was changed drastically: Double shock facilitation (20 ms interval) turned into depression and stimulus trains of a frequency as low as 1 Hz led to a drastic reduction of the response.2.Membrane potential was hyperpolarized.3.Duration of action potential was strongly increased.4.Threshold for the triggering of action potentials was shifted to more positive levels.5.IPSPs were prolonged and their shunting power enhanced.6.Repetitive spiking elicited by the application of bicuculline was reversibly abolished. All these effects had in common that cell excitability was lowered. It is concluded that MEL might influence epileptic seizure activity and should be further investigated as potential anticonvulsant.

Corticosterone Reduces Synaptic Inhibition in Rat Hippocampal and Neocortical Neurons in vitro

We examined the effect of corticosterone (10‐7 to 10‐5 M) on membrane properties and postsynaptic potentials, by means of intracellular recordings from neocortical and hippocampal CA1 pyramidal neurons of the intact adult rat in vitro. Corticosterone reduced both the early and the late components of the orthodromically‐evoked inhibitory postsynaptic potential in both structures. The glucocorticoid receptor antagonist RU 38486 (10‐6 M) prevented this effect in the hippocampus. In hippocampal, but not in neocortical pyramidal neurons, corticosterone reduced a depolarizing membrane transient evoked by a depolarizing current step and increased the threshold for eliciting action potentials evoked by depolarizing current pulses. Corticosterone did not detectably alter the afterhyperpolarization following repetitive neuronal discharges evoked by current injection, in either the neocortex or in the hippocampus. Excitatory postsynaptic potentials, action potentials, membrane potential and membrane input resistance were also unchanged.

Differences in baclofen-sensitivity between CA3 neurons and granule cells of the guinea pig hippocampus in vitro

In the slice preparation of the guinea pig hippocampus, the effects of (+/-) baclofen added to the Krebs-Ringer solution on dentate granule cells and CA3 pyramidal cells were investigated by means of intracellular recording techniques. In a 10-25 microM concentration, baclofen reduces the inhibitory postsynaptic potentials of the granule cells evoked by electrical stimulation of the perforant path and hyperpolarizes the granule cell membrane slightly. The reduction of both, the excitatory and inhibitory postsynaptic potentials of CA3 pyramidal cells evoked by mossy fiber stimulation, however, is accompanied by a strong hyperpolarization and conductance increase. Further, repetitive discharges of granule cells elicited in the presence of the convulsant bicuculline (25 microM) are hardly affected by baclofen (50 microM), whereas those of CA3 neurons are blocked.

Valproate enhances inhibitory postsynaptic potentials in hippocampal neurons in vitro

Effects of sodium valproate (0.5-10 mM) on hippocampal cells (CA3 pyramidal cells and granule cells) of the guinea pig in vitro were studied by intra- and extracellular recording. Inhibitory postsynaptic potentials were markedly and reversibly augmented. Their shunting action as well as duration increased by more than 150%. Effects of locally administered gamma-aminobutyric acid (GABA) did not change significantly. Membrane characteristics such as membrane potential, membrane input resistance and action potential did not alter. Valproate suppressed spontaneous spiking and repetitive discharges evoked by GABA antagonists. It is concluded that valproate enhances GABAergic synaptic transmission by a presynaptic mechanism. However, postsynaptic mechanisms might be involved in the limitation of repetitive firing.

(±)-β-Parachlorophenylglutamate selectively enhances the depolarizing response to l-homocysteic acid in neocortical neurons of the rat: evidence for a specific uptake system ☆

The effect of (+/-)-beta-parachlorophenylglutamate (CP) on depolarizations induced by iontophoretically applied L-glutamate, L-aspartate, L-homocysteate (L-HCA) and D-HCA was investigated in neurons of the rat neocortex in vitro. CP, a reported blocker of amino acid uptake, strongly enhanced L-HCA responses whereas responses to the other amino acids remained little affected. This action was observed irrespective of whether CP was administered iontophoretically or pneumatically from micropipettes. CP (5 mM) administered alone had no effect on membrane potential. These findings suggest the existence of a specific uptake system for L-HCA providing further evidence in favour of a possible function of L-HCA as an endogenous ligand for the N-methyl-D-aspartate receptor in the rat neocortex.