The intravenous anesthetic ketamine, representing a non- competitive NMDA-receptor antagonist with high affinity

(Ki~400nM), has unique pharmacological and clinical manifestations. As there is little evidence of ketamine to interact with the primary target of most anesthetics, the inhibitory GABA- gated Cl--channels (GABAA Rs), it is widely used to prevent interference with the GABAergic system. Here we report that ketamine enhances a tonic background conductance present in granula neurons of cerebellar slices. Effects were blocked by the competitive GABAA R antagonist bicuculline and the a6-specific inhibitor furosemide and were absent in cerebellar slices from a6-/- or [delta]-/- knockout mice, supporting the tonic background current to be due to extrasynaptic a6, b2, and [delta] subunits. Based on comparative studies in oocytes expressing various GABAA Rs, we conclude that ketamine modulates mainly those with a6 and [delta]?subunits; these were also directly activated. To dissect both mechanisms we prepared acutely dissociated granula neurons. Here, ketamine only potentiated GABA induced currents, most efficiently at low GABA concentrations with an EC50 of

~300mM. Responses at high GABA concentration were slightly inhibited; no direct activation was observed. Summarized, our data indicate subtypes of GABAA Rs to contribute to the atypical effects of ketamine at anesthetically relevant concentrations.