Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in alpha 7 nicotinic acetylcholine receptors

• Published in: European journal of pharmacology 2013-01, Vol.698 (1-3), p.228-234
• Main Authors: Moaddel, Ruin, Abdrakhmanova, Galia, Kozak, Joanna, Jozwiak, Krzysztof, Toll, Lawrence, Jimenez, Lucita, Rosenberg, Avraham, Tran, Thao, Xiao, Yingxian, Zarate, Carlos A, Wainer, Irving W
• Format: Article
• Language: English
• ISSN: 0014-2999
• DOI: 10.1016/j.ejphar.2012.11.023

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, IC sub(50)=55 plus or minus 6 nM, and that (2S,6S)-hydroxynorketamine, (2R,6R)-hydroxynorketamine and (R,S)-norketamine also inhibited alpha 7-nicotinic acetylcholine receptor function at concentrations less than or equal to 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 [ super(125)I]- alpha -bungarotoxin and [ super(3)H]-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, IC sub(50) 3.1 and 9.1 mu M, respectively, while (R,S)-dehydronorketamine, (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine were weak inhibitors, IC sub(50) >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 [ super(3)H]-MK-801. The calculated K sub(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.