title: Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors.
abstract: 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 α7 and α3β4 neuronal nicotinic acetylcholine receptors was investigated using patch-clamp techniques. The data indicated that (R,S)-dehydronorketamine inhibited acetylcholine-evoked currents in α7-nicotinic acetylcholine receptor, IC(50) = 55 ± 6 nM, and that (2S,6S)-hydroxynorketamine, (2R,6R)-hydroxynorketamine and (R,S)-norketamine also inhibited α7-nicotinic acetylcholine receptor function at concentrations ≤ 1 μM, 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 α7-nicotinic acetylcholine receptor ligands [(125)I]-α-bungarotoxin and [(3)H]-epibatidine indicating that (R,S)-dehydronorketamine is a negative allosteric modulator of the α7-nicotinic acetylcholine receptor. (R,S)-Ketamine and (R,S)-norketamine inhibited (S)-nicotine-induced whole-cell currents in cells expressing α3β4-nicotinic acetylcholine receptor, IC(50) 3.1 and 9.1 μM, respectively, while (R,S)-dehydronorketamine, (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine were weak inhibitors, IC(50) >100 μM. 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 [(3)H]-MK-801. The calculated K(i) values were 38.95 μM for (S)-dehydronorketamine, 21.19 μM for (2S,6S)-hydroxynorketamine and>100 μM for (2R,6R)-hydroxynorketamine. The results suggest that the inhibitory activity of ketamine metabolites at the α7-nicotinic acetylcholine receptor may contribute to the clinical effect of the drug.
authors.affiliation: Laboratory of Clinical Investigation, Division of Intramural Research Programs, National institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.forename: Galia
authors.initials: G
authors.lastname: Abdrakhmanova
authors.forename: Joanna
authors.initials: J
authors.lastname: Kozak
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jozwiak
authors.forename: Lawrence
authors.initials: L
authors.lastname: Toll
authors.forename: Lucita
authors.initials: L
authors.lastname: Jimenez
authors.forename: Avraham
authors.initials: A
authors.lastname: Rosenberg
authors.forename: Thao
authors.initials: T
authors.lastname: Tran
authors.forename: Yingxian
authors.initials: Y
authors.lastname: Xiao
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
authors.forename: Irving W
authors.initials: IW
authors.lastname: Wainer
mesh_terms: D000109:Acetylcholine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000777:Anesthetics / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D007649:Ketamine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D000777:Anesthetics; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D007649:Ketamine; D000109:Acetylcholine