Decreased Efficacy of GABAA-receptor modulation by midazolam in the kainate model of temporal lobe epilepsy.
OBJECTIVE
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 beta-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 beta-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.
Liefaard
Lia C
LC
Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands.
Gunput
Rou-Afza F
RA
Danhof
Meindert
M
Voskuyl
Rob A
RA
D000818:Animals; D001345:Autoradiography / Q000706:statistics & numerical data; D001611:Beta Rhythm / Q000187:drug effects / Q000706:statistics & numerical data; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000187:drug effects / Q000706:statistics & numerical data; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D005442:Flumazenil / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007608:Kainic Acid; D008874:Midazolam / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D013226:Status Epilepticus / Q000139:chemically induced; D016896:Treatment Outcome; D014316:Tritium / Q000378:metabolism
D011963:Receptors, GABA-A; D014316:Tritium; D005442:Flumazenil; D008874:Midazolam; D007608:Kainic Acid