Propofol modulation of [3H]flunitrazepam binding to GABAA receptors in guinea pig cerebral cortex

Binding of the radioligand [H-3]flunitrazepam to membranes prepared from the cerebral cortex of adult, male guinea pigs under equilibrium and non-equilibrium conditions was used to investigate the allosteric interaction between the intravenous general anesthetic propofol and the benzodiazepine site of the GABA, receptor. Propofol induced a potentiation of [H-3]flunitrazepam binding with an EC50 of 9 +/- 4 mu M. Propofol increased the affinity for [H-3]flunitrazepam binding with no change in maximal binding. Propofol did not change the rate constant of association for [H-3]flunitrazepam binding to cerebral cortical membranes. In contrast, the rate constant for dissociation of [H-3]flunitrazepam was significantly decreased in the presence of propofol. These data demonstrate that propofol increases the affinity of the benzodiazepine site of the GABA(A) receptor via a selective decrease in the rate constant for dissociation, and suggest a mechanism for the allosteric interaction between propofol and benzodiazepines at the GABA(A) receptor. (C) 1998 Elsevier Science B.V. All rights reserved.