POTENTIATION OF GAMMA-AMINOBUTYRIC ACID(A) RECEPTOR CL- CURRENT CORRELATES WITH IN-VIVO ANESTHETIC POTENCY

Ten general anesthetics of varying structure and potency were investig ated for possible modulatory effects on gamma-aminobutyric acid, (GABA (A)) receptors, using the voltage clamp technique. All 10 anesthetics studied were observed to prolong the duration of responses to exogenou sly applied GABA recorded in cultured rat hippocampal neurons. These m odulatory effects of the anesthetics occurred at pharmacologically rel evant concentrations. An excellent correlation exists between drug pot ency as modulators of the GABA(A) receptor and anesthetic potency in v ivo. These data suggest an alternative interpretation of the historica l association between anesthetic potency and lipophilicity. It is prop osed that hydrophobic binding sites on ligand-gated ion channel protei ns, such as the GABA(A) receptors, constitute a molecular target site for many general anesthetics.