BIOCHEMICAL EVALUATIONS OF THE EFFECTS OF LORECLEZOLE AND PROPOFOL ONTHE GABA(A) RECEPTOR IN RAT-BRAIN

The effects of loreclezole on the function of the gamma-aminobutyric a cid type A. (GABA(A)) receptor complex in rat cerebral cortical membra ne preparations were compared with those of propofol and diazepam. Lor eclezole and propofol modulated [H-3]muscimol binding and t-[S-35]buty lbicyclophosphorothionate ([S-35]TBPS) binding to washed and unwashed membranes with potencies and efficacies greater than those of diazepam . Loreclezole and propofol enhanced [H-3]flunitrazepam binding to wash ed membranes with efficacies lower than those of GABA and muscimol. Bo th loreclezole and propofol showed biphasic effects on [S-35]TBPS bind ing to washed membranes: at low concentrations (5 to 10 mu M), both dr ugs, with different efficacies, enhanced [S-35]TBPS binding whereas, a t higher concentrations (30 to 100 mu M), they inhibited this biochemi cal parameter. In contrast, diazepam enhanced [S-35]TBPS binding to wa shed membranes at all concentrations tested. The combination of lorecl ezole with GABA, at a concentration (0.3 mu M) that only slightly incr eased [S-35]TBPS binding to washed membranes, reversed the increase in binding elicited by loreclezole (5 to 10 mu M) and significantly pote ntiated the inhibitory effect exerted by higher concentrations (30 to 100 mu M) of this drug. Similar effects were observed with the combina tion of GABA and propofol. However, GABA had no effect on the enhancem ent of [S-35]TBPS binding induced by diazepam. The ability of GABA to reverse and potentiate the effects of loreclezole and propofol on [S-3 5]TBPS binding to washed membranes was shared by pentobarbital (200 mu M) and alphaxalone (3 mu M). These anesthetics showed greater efficac ies in combination with propofol than with loreclezole. These results suggest that, unlike diazepam, loreclezole and propofol may activate t he receptor-associated Cl- channel in the absence of GABA. Furthermore , the difference in the pharmacological profiles of loreclezole and pr opofol may result from their different effectiveness in activating the receptor Cl- channel directly.