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Enhancement of benzodiazepine binding sites following chronic treatment with flumazenil.

Pericić D, Jazvinsćak Jembrek M, Svob Strac D, Lazić J, Spoljarić IR

Ruder Bosković Institute, Laboratory for Molecular Neuropharmacology, Division of Molecular Medicine, P.O.B. 180, 10002 Zagreb, Croatia. pericic@irb.hr

The aim of this study was to improve our knowledge of the mechanisms leading to adaptive changes in gamma-aminobutyric acid(A) (GABA(A)) receptors following chronic drug treatment. Exposure (48 h) of human embryonic kidney (HEK 293) cells stably expressing recombinant alpha1beta2gamma2S GABA(A) receptors to the antagonist of benzodiazepine binding sites, flumazenil (5 microM), enhanced the maximum number (B(max)) and the equilibrium dissociation constant (K(d)) of [3H]flunitrazepam binding sites. The flumazenil-induced enhancement in B(max) was potentiated by GABA (50 microM) and reduced by the GABA(A) receptor antagonist, bicuculline (100 microM). Flumazenil-induced enhancement in K(d) was affected by neither of these treatments. GABA (50 microM) enhanced the density of [3H]flunitrazepam binding sites, and this enhancement was greater in the presence of diazepam (1 microM). The results suggest that chronic flumazenil treatment up-regulates in a bicuculline-sensitive manner benzodiazepine binding sites at stably expressed GABA(A) receptors.

Published 20 January 2005 in Eur J Pharmacol, 507(1): 7-13.
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