• Lia C Liefaard, Bart A Ploeger, Carla F M Molthoff, Hugo W A M de Jong, Jouke Dijkstra, Louise van der Weerd, Adriaan A Lammertsma, Meindert Danhof, and Rob A Voskuyl.
• Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands.
• Epilepsia. 2009 Jan 1;50(1):88-98.

PurposeThe purpose of the present investigation was to quantify alterations in GABA(A) receptor density in vivo in rats subjected to amygdala kindling.MethodsThe GABA(A) receptor density was quantified by conducting a [(11)C]flumazenil (FMZ) positron emission tomography (PET) study according to the full saturation method, in which each animal received a single injection of FMZ to fully saturate the GABA(A) receptors. Subsequently, the concentration-time curves of FMZ in blood [using high-pressure liquid chromatography with UV detector (HPLC-UV) or high-performance liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS)] and brain (with PET-scanning) were analyzed by population modeling using a pharmacokinetic model, containing expressions to describe the time course of FMZ in blood and brain.ResultsThe GABA(A) receptor density (B(max)) in kindled rats was decreased by 36% compared with controls. This is consistent with a reduction of 28% in electroencephalography (EEG) effect of midazolam in the same animal model, suggesting that a reduced number of GABA(A) receptors underlies the decreased efficacy of midazolam. Furthermore, receptor affinity (K(D)) was not changed, but the total volume of distribution in the brain (V(Br)), is increased to 178% of control after kindling, which might indicate an alteration in the transport of FMZ across the blood-brain barrier.ConclusionsBoth the GABA(A) receptor density (B(max)), and possibly also the blood-brain barrier transport of FMZ (V(Br)) are altered after kindling. Furthermore, this study indicates the feasibility of conducting PET studies for quantifying moderate changes in GABA(A) receptor density in a rat model of epilepsy in vivo.

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