Altered in vitro and in vivo flumazenil binding in human epileptogenic neocortex

In vitro and in vivo parameters of flumazenil (FMZ) binding were measured i n spiking and nonspiking neocortex identified by intraoperative electrocort icography in epileptic patients who underwent cortical resection for seizur e control. In vitro measures of receptor affinity (K-D), number (B-max) and laminar distribution for [H-3]-FMZ binding in the epileptic focus (n = 38) were compared to nonspiking cortex from a subgroup of the patients (n = 12 ) and to tissue obtained from trauma patients (n = 5). The in vitro binding parameters were compared to in vivo [C-11]-FMZ binding measured with posit ron emission tomography (PET) (n = 19). The B-max was higher in the 38 spik ing tissues as compared to the 12 nonspiking tissues (P =.012). Paired comp arison of spiking versus nonspiking binding in the 12 patients from whom no nspiking tissue was available showed increases in both K-D (P =.037) and B- max (P =.0047) in spiking cortex. A positive correlation was found between K-D and B-max values for 38 patients (r = 0.55, P < .0001), the magnitude o f the K-D, increase being twice that of the B-max increase. In addition, th ere was a significant correlation between the asymmetry indices of the in v ivo FMZ binding on PET and in vitro K-D of spiking cortex (n = 19, r = 0.52 , P = .02). The laminar distribution of [H-3]-FMZ showed increased FMZ bind ing in cortical layers V-VI in spiking cortex compared to nonspiking and co ntrol cortex. The increased receptor number in spiking cortical layers V-VI may be a compensatory mechanism to decreased GABAergic input. The increase d B-max in spiking cortex was accompanied by a larger decrease in the affin ity of FMZ for the receptor suggesting that decreased FMZ binding in the ep ileptic focus measured with PET is due to a decrease in the affinity of the tracer for the receptor.