1. Actions of lanthanide ions were examined on general anesthetic-induced currents mediated by the activation of gamma-aminobutyric acid-A receptors (GABAARs) in rat septal cholinergic neurons in primary culture, by means of a whole cell voltage-clamp technique. 2. La3+ enhanced a pentobarbital sodium (500 microM)-induced GABAAR current in a reversible and dose-dependent manner (median effective concentration = 15.7 microM; Hill coefficient = 1.58; 89% increase by 100 microM La3+). This action was independent of holding potentials (-34-26 mV), and was due to an increase in the apparent affinity for pentobarbital (295% increase with 100 microM La3+). 3. The action of La3+ on pentobarbital current was mimicked particularly by other lanthanide ions (Ce3+, Nd3+, Gd3+, Tb3+, Er3+, and Yb3+) and by Y3+ among a number of multivalent cations. There was no correlation between the potentiated proportions by lanthanide ions and their crystal ionic radii. 4. La3+ (100 microM) also augmented a GABAAR response evoked by either alpha-chloralose (500 microM), 2,6-diisopropylphenol (50 microM), or 3-alpha-hydroxy-5-alpha-pregnane-11,20-dione (20 microM) (144, 80, and 153% increase, respectively). 5. We suggest that the GABAAR channels on septal neurons are endowed with a novel "lanthanide site" whose activation results in a positive allosteric interaction with a binding site of the general anesthetics that is involved in a direct activation of GABAAR channels without any added exogenous GABA.