Propofol modulation of [ super(3)H]flunitrazepam binding to GABA sub(A) receptors in guinea pig cerebral cortex

Binding of the radioligand [ super(3) H ] 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 sub(A) receptor. Propofol induced a potentiation of [ super(3) H ] flunitrazepam binding with an EC sub(50) of 9 plus or minus 4 mu M. Propofol increased the affinity for [ super(3) H ] flunitrazepam binding with no change in maximal binding. Propofol did not change the rate constant of association for [ super(3) H ] flunitrazepam binding to cerebral cortical membranes. In contrast, the rate constant for dissociation of [ super(3) H ] flunitrazepam was significantly decreased in the presence of propofol. These data demonstrate that propofol increases the affinity of the benzodiazepine site of the GABA sub(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 sub(A) receptor.