Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors

The effect of the (R,S)-ketamine metabolites (R,S)-norketamine, (R,S)-dehydronorketamine, (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine on the activity of alpha 7 and alpha 3 beta 4 neuronal nicotinic acetylcholine receptors was investigated using patch-clamp techniques. The data indicated that (R,S)-dehydronorketamine inhibited acetylcholine-evoked currents in alpha 7-nicotinic acetylcholine receptor, IC50=55 +/- 6 nM, and that (2S,6S)-hydroxynorketamine, (2R,6R)-hydroxynorketamine and (R,S)-norketamine also inhibited alpha 7-nicotinic acetylcholine receptor function at concentrations <= 1 mu M, while (R,S)-ketamine was inactive at these concentrations. The inhibitory effect of (R,S)-dehydronorketamine was voltage-independent and the compound did not competitively displace selective alpha 7-nicotinic acetylcholine receptor ligands [I-125]-alpha-bungarotoxin and [H-3]-epibatidine indicating that (R,S)-dehydronorketamine is a negative allosteric modulator of the alpha 7-nicotinic acetylcholine receptor. (R,S)-Ketamine and (R,S)-norketamine inhibited (S)-nicotine-induced whole-cell currents in cells expressing alpha 3 beta 4-nicotinic acetylcholine receptor, IC50 3.1 and 9.1 mu M, respectively, while (R,S)-dehydronorketamine, (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine were weak inhibitors, IC50 > 100 mu M. The binding affinities of (R,S)-dehydronorketamine, (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine at the NMDA receptor were also determined using rat brain membranes and the selective NMDA receptor antagonist [H-3]-MK-801. The calculated K-i values were 38.95 mu M for (S)-dehydronorketamine, 21.19 mu M for (2S,6S)-hydroxynorketamine and > 100 mu M for (2R,6R)-hydroxynorketamine. The results suggest that the inhibitory activity of ketamine metabolites at the alpha 7-nicotinic acetylcholine receptor may contribute to the clinical effect of the drug. Published by Elsevier B.V.