On the Action of the Anti-Absence Drug Ethosuximide in the Rat and Cat Thalamus

Abstract

The action of ethosuximide (ETX) on Na+, K+, and Ca2+ currents and on tonic and burst-firing patterns was investigated in rat and cat thalamic neurons in vitro by using patch and sharp microelectrode recordings. In thalamocortical (TC) neurons of the rat dorsal lateral geniculate nucleus (LGN), ETX (0.75-1 mM) decreased the noninactivating Na+ current, INaP, by 60% but had no effect on the transient Na+ current. In TC neurons of the rat and cat LGN, the whole-cell transient outward current was not affected by ETX (up to 1 mM), but the sustained outward current was decreased by 39% at 20 mV in the presence of ETX (0.25-0.5 mM): this reduction was not observed in a low Ca2+ (0.5 mM) and high Mg2+ (8 mM) medium or in the presence of Ni2+ (1 mM) and Cd2+ (100 microM). In addition, ETX (up to 1 mM) had no effect on the low-threshold Ca2+ current, IT, of TC neurons of the rat ventrobasal (VB) thalamus and LGN and in neurons of the rat nucleus reticularis thalami nor on the high-threshold Ca2+ current in TC neurons of the rat LGN. Sharp microelectrode recordings in TC neurons of the rat and cat LGN and VB showed that ETX did not change the resting membrane potential but increased the apparent input resistance at potentials greater than -60 mV, resulting in an increase in tonic firing. In contrast, ETX decreased the number of action potentials in the burst evoked by a low-threshold Ca2+ potential. The frequency of the remaining action potentials in a burst also was decreased, whereas the latency of the first action potential was increased. Similar effects were observed on the burst firing evoked during intrinsic delta oscillations. These results indicate an action of ETX on INaP and on the Ca2+-activated K+ current, which explains the decrease in burst firing and the increase in tonic firing, and, together with the lack of action on low- and high-threshold Ca2+ currents, the results cast doubts on the hypothesis that a reduction of IT in thalamic neurons underlies the therapeutic action of this anti-absence medicine.

Molecular Targets for Antiepileptic Drug Development

“…For example, ethosuximide was claimed to reduce a sustained K ϩ current in thalamic neurons, an effect interpreted as a block of a Ca 2ϩ -activated K ϩ current. 154 In addition, pregabalin was reported to open ATP-sensitive K ϩ channels. 155 Lamotrigine, however, was found to reduce the amplitude of A-type K ϩ currents in cultured hippocampal neurons 156 and levetiracetam was reported to inhibit delayed rectifier but not A-type K ϩ currents in isolated hippocampal neurons.…”

“…73,154 Nevertheless, the effect on T-type currents is undoubtedly real, because it has been demonstrated in expressed human receptors 74 ; it is probably large enough to block slow oscillatory firing. Microinfusion of ethosuximide into the thalamus is, however, less effective at blocking spikeand-wave discharges than infusion into the somatosensory cortex, suggesting that molecular targets relating to the initiation of spikes in the cortex (e.g., Na ϩ channels, HCN channels) may be more important than thalamic T-type Ca 2ϩ channels.…”

Actions of U-92032, a T-Type Ca2+ Channel Antagonist, Support a Functional Linkage Between I T and Slow Intrathalamic Rhythms

“…8B) quickly (Ͻ30 min), compared with the slower, and more incomplete block by 1 M U-92032. Other cellular actions of ES have been proposed to contribute to the anti-oscillatory effects of succinimides and related compounds, including reductions in Ca 2ϩ -activated K ϩ and persistent Na ϩ currents (Leresche et al 1998). Such effects might alter neuronal excitability in ways independent of LTS bursts.…”

“…However, Leresche et al (1998) have recently shown that other cellular actions, reductions in persistent Na ϩ currents and/or Ca 2ϩ -dependent K ϩ currents, may play important roles in the anti-oscillatory effects of ES in thalamus. These and other findings have led to some controversy regarding the T-channel-dependent hypothesis of intrathalamic rhythmicity (reviewed in Crunelli and Leresche 2002;Huguenard 2002).…”

Pharmacological and Behavioral Characteristics of Interactions between Vigabatrin and Conventional Antiepileptic Drugs in Pentylenetetrazole-Induced Seizures in Mice: An Isobolographic Analysis

“…With respect to ESM's mechanism(s) of action, the advanced molecular and neurochemical studies have provided evidence that the drug preferentially binds to the inactivated state of low-threshold T-type Ca 2 þ channels and selectively inhibits pathological firing without any effect on normal neuronal activity (Coulter et al, 1989;Gomora et al, 2001). Moreover, it has been found that ESM decreases the Ca 2 þ -activated K þ current in thalamo-cortical neurons (Coulter et al, 1989) and partially reduces the noninactivating Na þ current (Leresche et al, 1998). All these changes in Na þ , K þ , and Ca 2 þ currents following the ESM administration are responsible for disrupting thalamo-cortical synchronized activity of neurons during spike and wave discharges in vivo (Crunelli and Leresche, 2002).…”