<p class="first" id="d11111257e95">Channel blocking, anti-oscillatory, and anti-epileptic
effects of clinically used
anti-absence substances (ethosuximide, valproate) and the T-type Ca2+ current (IT)
blocker mibefradil were tested by analyzing membrane currents in acutely isolated
local circuit interneurons and thalamocortical relay (TC) neurons, slow intrathalamic
oscillations in brain slices, and spike and wave discharges (SWDs) occurring in vivo
in Wistar Albino Glaxo rats from Rijswijk (WAG/Rij). Substance effects in vitro were
compared between WAG/Rij and a non-epileptic control strain, the ACI rats. Ethosuximide
(ETX) and valproate were found to block IT in acutely isolated thalamic neurons. Block
of IT by therapeutically relevant ETX concentrations (0.25-0.75 mM) was stronger in
WAG/Rij, although the maximal effect at saturating concentrations (>or=10 mM) was
stronger in ACI. Ethosuximide delayed the onset of the low threshold Ca2+ spike (LTS)
of neurons recorded in slice preparations. Mibefradil (>or=2 microM) completely
blocked
IT and the LTS, dampened evoked thalamic oscillations, and attenuated SWDs in vivo.
Computational modeling demonstrated that the complete effect of ETX can be replicated
by a sole reduction of IT. However, the necessary degree of IT reduction was not induced
by therapeutically relevant ETX concentrations. A combined reduction of IT, the persistent
sodium current, and the Ca2+ activated K+ current resulted in an LTS alteration resembling
the experimental observations. In summary, these results support the hypothesis of
IT reduction as part of the mechanism of action of anti-absence drugs and demonstrate
the ability of a specific IT antagonist to attenuate rhythmic burst firing and SWDs.
</p>