Ethosuximide modifies network excitability in the rat entorhinal cortex via an increase in GABA release

Stuart D Greenhill, Nicola H Morgan, Peter V Massey, Gavin L Woodhall, Roland S G Jones

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Abstract

Ethosuximide is the drug of choice for treating generalized absence seizures, but its mechanism of action is still a matter of debate. It has long been thought to act by disrupting a thalamic focus via blockade of T-type channels and, thus, generation of spike–wave activity in thalamocortical pathways. However, there is now good evidence that generalized absence seizures may be initiated at a cortical focus and that ethosuximide may target this focus. In the present study we have looked at the effect ethosuximide on glutamate and GABA release at synapses in the rat entorhinal cortex in vitro, using two experimental approaches. Whole-cell patch-clamp studies revealed an increase in spontaneous GABA release by ethosuximide concurrent with no change in glutamate release. This was reflected in studies that estimated global background inhibition and excitation from intracellularly recorded membrane potential fluctuations, where there was a substantial rise in the ratio of network inhibition to excitation, and a concurrent decrease in excitability of neurones embedded in this network. These studies suggest that, in addition to well-characterised effects on ion channels, ethosuximide may directly elevate synaptic inhibition in the cortex and that this could contribute to its anti-absence effects.
LanguageEnglish
Pages807-814
Number of pages8
JournalNeuropharmacology
Volume62
Issue number2
DOIs
StatusPublished - Feb 2012

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Ethosuximide
Entorhinal Cortex
gamma-Aminobutyric Acid
Absence Epilepsy
Glutamic Acid
Seizures
Ion Channels
Membrane Potentials
Synapses
Neurons
Pharmaceutical Preparations

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Ethosuximide modifies network excitability in the rat entorhinal cortex via an increase in GABA release. / Greenhill, Stuart D; Morgan, Nicola H; Massey, Peter V; Woodhall, Gavin L; Jones, Roland S G.

In: Neuropharmacology, Vol. 62, No. 2, 02.2012, p. 807-814.

Research output: Contribution to journalArticle

Greenhill, Stuart D ; Morgan, Nicola H ; Massey, Peter V ; Woodhall, Gavin L ; Jones, Roland S G. / Ethosuximide modifies network excitability in the rat entorhinal cortex via an increase in GABA release. In: Neuropharmacology. 2012 ; Vol. 62, No. 2. pp. 807-814
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