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Decreased Efficacy of GABA A ‐receptor Modulation by Midazolam in the Kainate Model of Temporal Lobe Epilepsy
Author(s) -
Liefaard Lia C.,
Gunput RouAfza F.,
Danhof Meindert,
Voskuyl Rob A.
Publication year - 2007
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1167.2007.01081.x
Subject(s) - kainate receptor , ex vivo , midazolam , flumazenil , status epilepticus , in vivo , kainic acid , epilepsy , pharmacokinetics , pharmacology , gabaa receptor , medicine , chemistry , endocrinology , receptor , biology , neuroscience , glutamate receptor , ampa receptor , sedation , microbiology and biotechnology
Summary: Purpose: The objective of this investigation was to characterize quantitatively the time‐dependent changes in midazolam (MDL) efficacy in the silent period after induction of status epilepticus (SE) in rats. The changes in MDL efficacy were correlated to changes in ex vivo GABA A ‐receptor expression. Methods: MDL efficacy was quantified by pharmacokinetic–pharmacodynamic (PK‐PD) modeling by using the β‐frequency of the EEG as PD end point. Two PK‐PD experiments were performed in each animal: the first experiment before and the second experiment at either day 4 or day 14 after SE. SE was induced by repetitive intraperitoneal injections with kainate. GABA A ‐receptor expression was determined by ex vivo autoradiography with [ 3 H]flumazenil. Results: The concentration versus EEG effect relation of midazolam was successfully described by the sigmoidal E max model. The maximal effect on the β‐frequency of the EEG ( E max ) was reduced to 51.6 ± 35.6% and 25.8 ± 33.7% of the original value at 4 and 14 days after induction of SE. The ex vivo study with [ 3 H]flumazenil showed that the observed reductions in E max were paralleled by a reduction in GABA A ‐receptor density. Conclusions: The efficacy of MDL is decreased in the silent period after SE, which can be partly accounted for by a reduction in GABA A ‐receptor density.