Effects of ketamine and its metabolites on ion currents in differentiated hippocampal H19-7 neuronal cells and in HEK293T cells transfected with α-hslo subunit

Ketamine (KT), a dissociative anesthetic, is known to induce schizophrenia-like psychosis. The percentage of KT abuse has recently grown fast despite KT being a controlled drug. The mechanism of KT actions is related to the inhibition of NMDA receptors. Whether KT produces other effects on ion currents in hippocampal neurons remains unclear. In this study, we attempted to evaluate the possible effects of KT and other related compounds on ion currents in hippocampal neuron-derived H19-7 cells. This drug exerted an inhibitory effect on Ca2+-activated K+ current (I-K(Ca)) in these cells with an IC50 value of 274 mu M. Pimaric acid (30 mu M) or abietic acid (30 mu M), known to stimulate large-conductance' Ca2+-activated K+ channels, reversed KT-induced inhibition of I-K(Ca). In HEK293T cells expressing alpha-human slowpoke, KT-induced inhibition of I-K(Ca) still existed. Dehydronorketamine (300 mu M) had little or no effect on the I-K(Ca) amplitude, while norketamine (300 mu M) slightly but significantly suppressed it. In inside-out configuration, KT applied to the intracellular face of the membrane did not alter single-channel conductance of large-conductance Ca2+-activated K+ (BKCa) channels; however, it did significantly reduce the probability of channel openings. Addition of KT was effective in depressing the peak amplitude of voltage-gated Na+ current. Moreover, the presence of KT was noted to enhance the amplitude of membrane electroporation-induced inward currents (I-MEP) in differentiated H19-7 cells. KT-stimulated I-MEP was reversed by further application of LaCl3 (100 mu M), but not by NMDA (30 mu M). The modulations by this compound of ion channels may contribute to the underlying mechanisms through which KT and its metabolites influence the electrical behavior of hippocampal neurons if similar findings occur in vivo. (C) 2012 Elsevier Inc. All rights reserved.