Sub-anesthetic concentrations of (R, S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
(2R,6R)-HNK has binding affinity Ki and IC50 greater than 100 μM with 24% inhibition at 100 μM, and fails to impact NMDA-evoked currents in CA1 interneurons.
“(2R,6R)-HNK has a binding affinity (Ki) and IC50 greater than 100 μM with 24% inhibition at 100 μM, and fails to impact NMDA-evoked currents in CA1 interneurons (Moaddel et al., 2013; Morris et al., 2017; Zanos et al., 2016).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Moaddel et al., 2013
Results §3.3 reports an NMDA-receptor binding Ki >100 μM for (2R,6R)-HNK. The Abstract reports IC50 >100 μM for inhibition of α3β4 nicotinic-receptor currents, not NMDA-evoked currents. Our copy does not report 24% inhibition at 100 μM or measurements of NMDA-evoked currents in CA1 interneurons; its NMDA binding assay used rat brain membranes (Methods §2.6; page numbers unavailable). (LLM, conf=0.88)
Experimental — accuracy not yet measured(2R,6R)-HNK does not displace MK-801 binding to NMDARs at 10 μM.
“its inability to displace MK-801 binding to NMDARs (10 μM).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Moaddel et al., 2013
Results §3.3 reports that (2R,6R)-HNK had very weak affinity in an MK-801 displacement assay (Ki >100 μM), consistent with little displacement at 10 μM. It does not report a displacement result specifically for (2R,6R)-HNK at 10 μM; Methods §2.6 uses 10 μM for unlabeled MK-801, not HNK. (LLM, conf=0.84)
Experimental — accuracy not yet measured(S)-ketamine has approximately 4-fold greater affinity/potency at inhibiting NMDAR compared to (R)-ketamine.
“(S)-ketamine has ~4-fold greater affinity/potency at inhibiting the NMDAR compared to its (R)-ketamine enantiomer 13, 111–115.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [112]
[3H]-MK-801 binding displacement studies showed affinity of (2R,6R)-HNK to displace MK-801 from NMDAR is >100 μM, and that of (2S,6S)-HNK is 7-20 μM.
“[3H]-MK-801 binding displacement studies showed that the affinity of (2R,6R)-HNK to displace MK-801 from the NMDAR is >100 μM, and that of (2S,6S)-HNK is 7–20 μM 111, 112.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [112]
At relevant concentrations (10 mg/kg or brain Cmax = ~10 μmol/kg in mice), (2R,6R)-HNK does not appear to inhibit the NMDAR.
“Important for the mechanism of action of (2R,6R)-HNK as an antidepressant (and thus ketamine’s action) is the fact that at relevant concentrations (i.e., 10 mg/kg or brain Cmax = ~10 μmol/kg in mice), (2R,6R)-HNK does not appear to inhibit the NMDAR.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [112]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist.
Wong, E. H. F., Kemp, J. A., Priestley, T., Knight, A. R., Woodruff, G. N., & Iversen, L. L. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.18.7104 · Cited by 1,820 · see citing works
X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel
Nury, H., Van Renterghem, C., Weng, Y., Tran, A., Baaden, M., Dufresne, V., Changeux, J.-P., Sonner, J. M., Delarue, M., & Corringer, P.-J. (2011) · Nature · doi:10.1038/nature09647 · Cited by 412 · see citing works
Zarate, C. A., Brutsche, N., Laje, G., Luckenbaugh, D. A., Venkata, S. L. V., Ramamoorthy, A., Moaddel, R., & Wainer, I. W. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.03.004 · Cited by 282 · see citing works
Self-citationNicotine receptors and depression: revisiting and revising the cholinergic hypothesis
Mineur, Y. S., & Picciotto, M. R. (2010) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2010.09.004 · Cited by 277 · see citing works
Analysis of Mecamylamine Stereoisomers on Human Nicotinic Receptor Subtypes
Papke, R. L., Sanberg, P. R., & Shytle, R. D. (2001) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)29581-1 · Cited by 271 · see citing works
Ebert, B., Mikkelsen, S. S., Thorkildsen, C., & Borgbjerg, F. M. (1997) · European Journal of Pharmacology · doi:10.1016/s0014-2999(97)01116-3 · Cited by 270 · see citing works
Xiao, Y., Meyer, E. L., Thompson, J. M., Surin, A. M., Wroblewski, J. T., & Kellar, K. J. (1998) · Molecular Pharmacology · doi:10.1124/mol.54.2.322 · Cited by 247 · see citing works
Self-citationPhilip, N. S., Carpenter, L. L., Tyrka, A. R., & Price, L. H. (2010) · Psychopharmacology · doi:10.1007/s00213-010-1932-6 · Cited by 185 · see citing works
Ketamine: new uses for an old drug?
Hirota, K., & Lambert, D. G. (2011) · British Journal of Anaesthesia · doi:10.1093/bja/aer221 · Cited by 160 · see citing works
Yamakura, T., Chavez-Noriega, L. E., & Harris, R. A. (2000) · Anesthesiology · doi:10.1097/00000542-200004000-00033 · Cited by 141 · see citing works
Metabolism of Ketamine Stereoisomers by Human Liver Microsomes
Kharasch, E. D., & Labroo, R. B. (1992) · Anesthesiology · doi:10.1097/00000542-199212000-00022 · Cited by 140 · see citing works
Zhao, X., Venkata, S. L. V., Moaddel, R., Luckenbaugh, D. A., Brutsche, N. E., Ibrahim, L., Zarate Jr, C. A., Mager, D. E., & Wainer, I. W. (2012) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2012.04198.x · Cited by 137 · see citing works
Self-citationLeung, L. Y., & Baillie, T. A. (1986) · Journal of Medicinal Chemistry · doi:10.1021/jm00161a043 · Cited by 135 · see citing works
Stereoselective and regiospecific hydroxylation of ketamine and norketamine
Desta, Z., Moaddel, R., Ogburn, E. T., Xu, C., Ramamoorthy, A., Venkata, S. L. V., Sanghvi, M., Goldberg, M. E., Torjman, M. C., & Wainer, I. W. (2012) · Xenobiotica · doi:10.3109/00498254.2012.685777 · Cited by 114 · see citing works
Self-citationCoates, K., & Flood, P. D. (2001) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0704315 · Cited by 114 · see citing works
Moaddel, R., Venkata, S. L. V., Tanga, M. J., Bupp, J. E., Green, C. E., Iyer, L., Furimsky, A., Goldberg, M. E., Torjman, M. C., & Wainer, I. W. (2010) · Talanta · doi:10.1016/j.talanta.2010.08.005 · Cited by 108 · see citing works
Self-citationAdams, J. D., Jr., Baillie, T. A., Trevor, A. J., & Castagnoli, N. (1981) · Journal of Mass Spectrometry · doi:10.1002/bms.1200081103 · Cited by 105 · see citing works
Bolze, S., & Boulieu, R. (1998) · Clinical Chemistry · doi:10.1093/clinchem/44.3.560 · Cited by 71 · see citing works
Woolf, T. F., & Adams, J. D., Jr. (1987) · Xenobiotica · doi:10.3109/00498258709043993 · Cited by 65 · see citing works
Turfus, S. C., Parkin, M. C., Cowan, D., Halket, J. M., Smith, N. W., Braithwaite, R. A., Elliot, S. P., Steventon, G. B., & Kicman, A. T. (2009) · Drug Metabolism and Disposition · doi:10.1124/dmd.108.026328 · Cited by 57 · see citing works
Moaddel, R., Jóźwiak, K., Yamaguchi, R., & Wainer, I. W. (2005) · Analytical Chemistry · doi:10.1021/ac0504464 · Cited by 40 · see citing works
Self-citationXiao, Y., Abdrakhmanova, G. R., Baydyuk, M., Hernandez, S. C., & Kellar, K. J. (2009) · Acta Pharmacologica Sinica · doi:10.1038/aps.2009.69 · Cited by 23 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
NMDAR inhibition-independent antidepressant actions of ketamine metabolites
Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., Elmer, G. I., Alkondon, M., Yuan, P., Pribut, H. J., Singh, N. S., et al. (2016) · Nature · doi:10.1038/nature17998 · Cited by 1,609 · see citing works
Self-citationKetamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms
Zanos, P., Moaddel, R., Morris, P. J., Riggs, L. M., Highland, J. N., Georgiou, P., Pereira, E. F. R., Albuquerque, E. X., Thomas, C. J., Zarate, C. A., et al. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.015198 · Cited by 1,260 · see citing works
Self-citationMechanisms of ketamine action as an antidepressant
Zanos, P., & Gould, T. D. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.255 · Cited by 1,127 · see citing works
R (−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine
Zhang, J.-C., Li, S.-X., & Hashimoto, K. (2014) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2013.11.033 · Cited by 357 · see citing works
Hashimoto, K. (2019) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12902 · Cited by 335 · see citing works
Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review
Molero, P., Ramos-Quiroga, J. A., Martin-Santos, R., Calvo-Sánchez, E., Gutiérrez-Rojas, L., & Meana, J. J. (2018) · CNS Drugs · doi:10.1007/s40263-018-0519-3 · Cited by 280 · see citing works
Gregorio, D. D., Aguilar‐Valles, A., Preller, K. H., Heifets, B. D., Hibicke, M., Mitchell, J., & Gobbi, G. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.1659-20.2020 · Cited by 261 · see citing works
Ketamine: NMDA Receptors and Beyond
Zorumski, C. F., Izumi, Y., & Mennerick, S. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.1547-16.2016 · Cited by 254 · see citing works
Aleksandrova, L. R., Phillips, A. G., & Wang, Y. T. (2017) · Journal of Psychiatry and Neuroscience · doi:10.1503/jpn.160175 · Cited by 228 · see citing works
KETAMINE'S MECHANISM OF ACTION: A PATH TO RAPID‐ACTING ANTIDEPRESSANTS
Abdallah, C. G., Adams, T. G., Kelmendi, B., Esterlis, I., Sanacora, G., & Krystal, J. H. (2016) · Depression and Anxiety · doi:10.1002/da.22501 · Cited by 206 · see citing works
Ketamine and phencyclidine: the good, the bad and the unexpected
Lodge, D., & Mercier, M. S. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13222 · Cited by 184 · see citing works
Effects of a ketamine metabolite on synaptic NMDAR function
Suzuki, K., Nosyreva, E., Hunt, K. W., Kavalali, E. T., & Monteggia, L. M. (2017) · Nature · doi:10.1038/nature22084 · Cited by 180 · see citing works
Convergent Mechanisms Underlying Rapid Antidepressant Action
Zanos, P., Thompson, S. M., Duman, R. S., Zarate, C. A., & Gould, T. D. (2018) · CNS Drugs · doi:10.1007/s40263-018-0492-x · Cited by 171 · see citing works
Self-citationMechanisms of ketamine and its metabolites as antidepressants
Hess, E. M., Riggs, L. M., Michaelides, M., & Gould, T. D. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114892 · Cited by 169 · see citing works
Niciu, M. J., Henter, I. D., Luckenbaugh, D. A., Zarate, C. A., & Charney, D. S. (2014) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-011613-135950 · Cited by 161 · see citing works
Self-citationLumsden, E. W., Troppoli, T. A., Myers, S. J., Zanos, P., Aracava, Y., Kehr, J., Lovett, J., Kim, S., Wang, F.-H., Schmidt, S., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1816071116 · Cited by 158 · see citing works
Self-citationZanos, P., Highland, J. N., Stewart, B. W., Georgiou, P., Jenne, C. E., Lovett, J., Morris, P. J., Thomas, C. J., Moaddel, R., Zarate, C. A., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1819540116 · Cited by 152 · see citing works
Self-citationMechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse
Korpi, E. R., den Hollander, B., Farooq, U., Vashchinkina, E., Rajkumar, R., Nutt, D. J., Hyytiä, P., & Dawe, G. S. (2015) · Pharmacological Reviews · doi:10.1124/pr.115.010967 · Cited by 148 · see citing works
Therapeutic Potential of α7 Nicotinic Acetylcholine Receptors
Bertrand, D., Lee, C., Flood, D. G., Marger, F., & Donnelly‐Roberts, D. L. (2015) · Pharmacological Reviews · doi:10.1124/pr.113.008581 · Cited by 139 · see citing works
Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants
Gould, T. D., Zarate, C. A., & Thompson, S. M. (2019) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010617-052811 · Cited by 133 · see citing works
Self-citationPaul, R. K., Singh, N. S., Khadeer, M., Moaddel, R., Sanghvi, M., Green, C. E., O’Loughlin, K., Torjman, M. C., Bernier, M., & Wainer, I. W. (2014) · Anesthesiology · doi:10.1097/aln.0000000000000285 · Cited by 115 · see citing works
Self-citationCan, A., Zanos, P., Moaddel, R., Kang, H. J., Dossou, K. S. S., Wainer, I. W., Cheer, J. F., Frost, D. O., Huang, X.-P., & Gould, T. D. (2016) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.116.235838 · Cited by 115 · see citing works
Self-citationRecent insights into the mode of action of memantine and ketamine
Johnson, J. W., Glasgow, N. G., & Povysheva, N. V. (2014) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2014.11.006 · Cited by 117 · see citing works
Classics in Chemical Neuroscience: Ketamine
Tyler, M. W., Yourish, H. B., Ionescu, D. F., & Haggarty, S. J. (2017) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.7b00074 · Cited by 106 · see citing works
Patrizi, A., Picard, N., Simon, A. J., Gunner, G., Centofante, E., Andrews, N. A., & Fagiolini, M. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.08.018 · Cited by 100 · see citing works
Silote, G. P., Sartim, A. G., Sales, A. J., Eskelund, A., Guimarães, F. S., Wegener, G., & Joca, S. R. L. (2019) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2019.04.006 · Cited by 93 · see citing works
Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications
Highland, J. N., Zanos, P., Riggs, L. M., Georgiou, P., Clark, S. M., Morris, P. J., Moaddel, R., Thomas, C. J., Zarate, C. A., Pereira, E. F. R., et al. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000149 · Cited by 92 · see citing works
Self-citationMorris, P. J., Moaddel, R., Zanos, P., Moore, C. E., Gould, T., Zarate, C. A., & Thomas, C. J. (2017) · Organic Letters · doi:10.1021/acs.orglett.7b02177 · Cited by 83 · see citing works
Self-citationdu Jardin, K. G., Liebenberg, N., Müller, H. K., Elfving, B., Sánchez, C., & Wegener, G. (2016) · Psychopharmacology · doi:10.1007/s00213-016-4327-5 · Cited by 85 · see citing works
Farmer, C. A., Gilbert, J. R., Moaddel, R., George, J., Adeojo, L., Lovett, J., Nugent, A. C., Kadriu, B., Yuan, P., Gould, T. D., et al. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-0663-6 · Cited by 85 · see citing works
Self-citationZanos, P., Highland, J. N., Liu, X., Troppoli, T. A., Georgiou, P., Lovett, J., Morris, P. J., Stewart, B. W., Thomas, C. J., Thompson, S. M., et al. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14683 · Cited by 82 · see citing works
Self-citationThe anterior cingulate cortex as a key locus of ketamine’s antidepressant action
Alexander, L., Jelen, L. A., Mehta, M. A., & Young, A. H. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.05.003 · Cited by 83 · see citing works
Effect fingerprinting of new psychoactive substances (NPS): What can we learn from in vitro data?
Hondebrink, L., Zwartsen, A., & Westerink, R. H. S. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.10.022 · Cited by 80 · see citing works
Sałat, K., Siwek, A., Starowicz, G., Librowski, T., Nowak, G., Drabik, U., Gajdosz, R., & Popik, P. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.07.037 · Cited by 77 · see citing works
Ma, J., Wang, F., Wang, J., Wang, P., Dou, X., Yao, S., & Lin, Y. (2023) · Drug Design Development and Therapy · doi:10.2147/dddt.s406568 · Cited by 76 · see citing works
Esketamine: new hope for the treatment of treatment-resistant depression? A narrative review
Salahudeen, M. S., Wright, C. M., & Peterson, G. M. (2020) · Therapeutic Advances in Drug Safety · doi:10.1177/2042098620937899 · Cited by 72 · see citing works
The clinical toxicology of ketamine
Schep, L. J., Slaughter, R. J., Watts, M., Mackenzie, E., & Gee, P. (2023) · Clinical Toxicology · doi:10.1080/15563650.2023.2212125 · Cited by 74 · see citing works
Esketamine: a glimmer of hope in treatment-resistant depression
Kaur, U., Pathak, B. K., Singh, A., & Chakrabarti, S. S. (2019) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-019-01084-z · Cited by 70 · see citing works
Khlestova, E., Johnson, J. W., Krystal, J. H., & Lisman, J. E. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.1203-16.2016 · Cited by 70 · see citing works
Ketamine and its metabolites: Potential as novel treatments for depression
Zhang, K., Yao, Y., & Hashimoto, K. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109305 · Cited by 69 · see citing works
Ketamine as a therapeutic agent for depression and pain: mechanisms and evidence
Subramanian, S., Haroutounian, S., Palanca, B. J. A., & Lenze, E. J. (2022) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2022.120152 · Cited by 68 · see citing works
Pradhan, B., Mitrev, L. V., Moaddel, R., & Wainer, I. W. (2018) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2018.03.006 · Cited by 63 · see citing works
Self-citationHighland, J. N., Morris, P. J., Zanos, P., Lovett, J., Ghosh, S., Wang, A. Q., Zarate, C. A., Thomas, C. J., Moaddel, R., & Gould, T. D. (2019) · Journal of Psychopharmacology · doi:10.1177/0269881118812095 · Cited by 62 · see citing works
Self-citationKetamine for depression: evidence, challenges and promise
Zarate, C. A., & Niciu, M. J. (2015) · World Psychiatry · doi:10.1002/wps.20269 · Cited by 60 · see citing works
Self-citationKetamine Blocks Morphine-Induced Conditioned Place Preference and Anxiety-Like Behaviors in Mice
McKendrick, G., Garrett, H., Jones, H. E., McDevitt, D. S., Sharma, S., Silberman, Y., & Graziane, N. (2020) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2020.00075 · Cited by 58 · see citing works
Lavender, E., Hirasawa-Fujita, M., & Domino, E. F. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.112631 · Cited by 56 · see citing works
Kim, S. W., Rush, B. S., & Rice, T. (2020) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-020-01542-3 · Cited by 60 · see citing works
Zorumski, C. F., Nagele, P., Mennerick, S., & Conway, C. R. (2015) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2015.00172 · Cited by 57 · see citing works
Nikiforuk, A., Kos, T., Hołuj, M., Potasiewicz, A., & Popik, P. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.07.034 · Cited by 55 · see citing works
du Jardin, K. G., Müller, H. K., Elfving, B., Dale, E., Wegener, G., & Sánchez, C. (2016) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2016.05.007 · Cited by 54 · see citing works
The neurophysiology of ketamine: an integrative review
McMillan, R. L., & Muthukumaraswamy, S. D. (2020) · Reviews in the Neurosciences · doi:10.1515/revneuro-2019-0090 · Cited by 49 · see citing works
Targeting metaplasticity mechanisms to promote sustained antidepressant actions
Brown, K. A., & Gould, T. D. (2024) · Molecular Psychiatry · doi:10.1038/s41380-023-02397-1 · Cited by 49 · see citing works
du Jardin, K. G., Liebenberg, N., Cajina, M., Müller, H. K., Elfving, B., Sanchez, C., & Wegener, G. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00978 · Cited by 47 · see citing works
Target deconvolution studies of (2R,6R)-hydroxynorketamine: an elusive search
Bonaventura, J., Gomez, J. L., Carlton, M. L., Lam, S., Sánchez‐Soto, M., Morris, P. J., Moaddel, R., Kang, H. J., Zanos, P., Gould, T. D., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01673-w · Cited by 46 · see citing works
Self-citationKetamine in the Past, Present, and Future: Mechanisms, Metabolites, and Toxicity
Schwenk, E. S., Pradhan, B., Nalamasu, R., Stolle, L., Wainer, I. W., Cirullo, M., Olson, A., Pergolizzi, J. V., Torjman, M. C., & Viscusi, E. R. (2021) · Current Pain and Headache Reports · doi:10.1007/s11916-021-00977-w · Cited by 44 · see citing works
Self-citationGarner, R. M., Gopalakrishnan, S., McCauley, J. A., Bednar, R. A., Gaul, S. L., Mosser, S. D., Kiss, L., Lynch, J. J., Patel, S., Fandozzi, C. M., et al. (2015) · Pharmacology Research & Perspectives · doi:10.1002/prp2.198 · Cited by 42 · see citing works
Recent Advances in the Discovery of Nicotinic Acetylcholine Receptor Allosteric Modulators
Manetti, D., Dei, S., Arias, H. R., Braconi, L., Gabellini, A., Teodori, E., & Romanelli, M. N. (2023) · Molecules · doi:10.3390/molecules28031270 · Cited by 41 · see citing works
Ketamine: The final frontier or another depressing end?
Sial, O. K., Parise, E. M., Parise, L. F., Gnecco, T., & Bolaños‐Guzmán, C. A. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.112508 · Cited by 40 · see citing works
Moaddel, R., Sanghvi, M., Dossou, K. S. S., Ramamoorthy, A., Green, C., Bupp, J. E., Swezey, R. R., O’Loughlin, K. G., & Wainer, I. W. (2015) · Pharmacology Research & Perspectives · doi:10.1002/prp2.157 · Cited by 41 · see citing works
Self-citationBeyond Ketamine: New Approaches to the Development of Safer Antidepressants
Chaki, S. (2017) · Current Neuropharmacology · doi:10.2174/1570159x15666170221101054 · Cited by 40 · see citing works
Smith-Apeldoorn, S. Y., Veraart, J. K. E., Kamphuis, J., van Asselt, A. D. I., Touw, D. J., Rot, M. A. H., & Schoevers, R. A. (2019) · BMC Psychiatry · doi:10.1186/s12888-019-2359-1 · Cited by 42 · see citing works
What is hydroxynorketamine and what can it bring to neurotherapeutics?
Singh, N., Zarate, C. A., Moaddel, R., Bernier, M., & Wainer, I. W. (2014) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2014.971760 · Cited by 38 · see citing works
Self-citationIngram, R., Kang, H., Lightman, S., Jane, D. E., Bortolotto, Z. A., Collingridge, G. L., Lodge, D., & Volianskis, A. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.06.008 · Cited by 36 · see citing works
Sullivan, K. G., & Levin, M. G. (2016) · Journal of Anatomy · doi:10.1111/joa.12467 · Cited by 34 · see citing works
Repurposing of Drugs–The Ketamine Story
Das, J. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01193 · Cited by 35 · see citing works
Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J. M., Elmer, G. I., Alkondon, M., Yuan, P., Pribut, H. J., Singh, N., et al. (2017) · Nature · doi:10.1038/nature22085 · Cited by 34 · see citing works
Self-citationZarate, C. A., & Machado‐Vieira, R. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.249 · Cited by 33 · see citing works
Self-citationOkada, M., Kawano, Y., Fukuyama, K., Motomura, E., & Shiroyama, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21217951 · Cited by 32 · see citing works
Mechanisms of the Rapid Effects of Ketamine on Depression and Sleep Disturbances: A Narrative Review
Song, B., & Zhu, J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.782457 · Cited by 31 · see citing works
Xie, Y.-G., Alexander, G. M., Schwartzman, R. J., Singh, N., Torjman, M. C., Goldberg, M. E., Wainer, I. W., & Moaddel, R. (2013) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2013.10.028 · Cited by 31 · see citing works
Self-citationA New Paradigm for Achieving a Rapid Antidepressant Response
Malhi, G. S., Morris, G., Bell, E., & Hamilton, A. (2020) · Drugs · doi:10.1007/s40265-020-01303-1 · Cited by 30 · see citing works
Singh, N., Paul, R. K., Ramamoorthy, A., Torjman, M. C., Moaddel, R., Bernier, M., & Wainer, I. W. (2013) · Cellular Signalling · doi:10.1016/j.cellsig.2013.08.025 · Cited by 30 · see citing works
Self-citationOkada, M., Fukuyama, K., Nakano, T., & Ueda, Y. (2019) · Biomolecules · doi:10.3390/biom9110746 · Cited by 29 · see citing works
Lester, H. A., Lavis, L. D., & Dougherty, D. A. (2015) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2015.14121537 · Cited by 29 · see citing works
Michaëlsson, H., Andersson, M., Svensson, J., Karlsson, L., Ehn, J., Culley, G. R., Engström, A., Bergström, N., Savvidi, P., Kuhn, H. G., et al. (2018) · Acta Physiologica · doi:10.1111/apha.13211 · Cited by 29 · see citing works
Sandbaumhüter, F. A., Theurillat, R., Bektas, R. N., Kutter, A. P. N., Bettschart‐Wolfensberger, R., & Thormann, W. (2016) · Journal of Chromatography A · doi:10.1016/j.chroma.2016.07.060 · Cited by 27 · see citing works
Highland, J. N., Morris, P. J., Konrath, K. M., Riggs, L. M., Hagen, N. R., Zanos, P., Powels, C. F., Moaddel, R., Thomas, C. J., Wang, A. Q., et al. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00761 · Cited by 27 · see citing works
Self-citationA circuit mechanism for decision-making biases and NMDA receptor hypofunction
Cavanagh, S. E., Lam, N. H., Murray, J. D., Hunt, L. T., & Kennerley, S. W. (2020) · eLife · doi:10.7554/elife.53664 · Cited by 27 · see citing works
Acetylcholine and metacognition during sleep
Gott, J. A., Stücker, S., Kanske, P., Haaker, J., & Dresler, M. (2024) · Consciousness and Cognition · doi:10.1016/j.concog.2023.103608 · Cited by 25 · see citing works
An integrative view on the cell-type-specific mechanisms of ketamine's antidepressant actions
Lewis, V., Rurak, G. M., Salmaso, N., & Aguilar‐Valles, A. (2024) · Trends in Neurosciences · doi:10.1016/j.tins.2023.12.004 · Cited by 27 · see citing works
Singh, N. S., Rutkowska, E., Plazinska, A., Khadeer, M., Moaddel, R., Jozwiak, K., Bernier, M., & Wainer, I. W. (2016) · PLOS ONE · doi:10.1371/journal.pone.0149499 · Cited by 23 · see citing works
Self-citationVeen, C., Jacobs, G. E., Philippens, I. H. C. H. M., & Vermetten, E. H. G. J. M. (2018) · Current topics in behavioral neurosciences · doi:10.1007/7854_2017_34 · Cited by 23 · see citing works
Vázquez-Gómez, E., Arias, H. R., Feuerbach, D., Miranda‐Morales, M., Mihailescu, S., Targowska‐Duda, K. M., Jóźwiak, K., & García‐Colunga, J. (2014) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2014.06.059 · Cited by 20 · see citing works
Aleksandrova, L. R., Wang, Y. T., & Phillips, A. G. (2017) · Chronic Stress · doi:10.1177/2470547017743511 · Cited by 21 · see citing works
Lewis, V., Rodrigue, B., Arsenault, E., Zhang, M., Taghavi‐Abkuh, F., Silva, W. C. C., Myers, M., Matta‐Camacho, E., & Aguilar‐Valles, A. (2022) · Journal of Neurochemistry · doi:10.1111/jnc.15652 · Cited by 20 · see citing works
Boucherie, D. E., Reneman, L., Ruhé, H. G., & Schrantee, A. (2023) · NeuroImage Clinical · doi:10.1016/j.nicl.2023.103517 · Cited by 20 · see citing works
Phillips, A. G., Geyer, M. A., & Robbins, T. W. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.01.014 · Cited by 19 · see citing works
Ren, L., Zhang, H., Tao, W., Chen, Y., Zou, Z., Guo, X., Shen, Q., Feng, Q., & Hu, J. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.896628 · Cited by 19 · see citing works
Esketamine in depression: putative biomarkers from clinical research
Johnston, J. N., Zarate, C. A., & Kvarta, M. D. (2024) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-024-01865-1 · Cited by 18 · see citing works
Self-citationLilius, T. O., Viisanen, H., Jokinen, V., Niemi, M., Kalso, E. A., & Rauhala, P. V. (2017) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.12941 · Cited by 18 · see citing works
Biosensors Show the Pharmacokinetics of S-Ketamine in the Endoplasmic Reticulum
Bera, K., Kamajaya, A., Shivange, A. V., Muthusamy, A. K., Nichols, A. L., Borden, P. M., Grant, S. N., Jeon, J., Lin, E., Bishara, I., et al. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00499 · Cited by 18 · see citing works
Gagne, C., Piot, A., & Brake, W. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.797577 · Cited by 14 · see citing works
Sub-anesthetic doses of ketamine attenuate nicotine self-administration in rats
Rezvani, A. H., Tizabi, Y., Slade, S. K., Getachew, B., & Levin, E. D. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2018.01.022 · Cited by 18 · see citing works
Dextromethorphan and memantine after ketamine analgesia: a randomized control trial
Martin, E., Sorel, M., Morel, V., Marcaillou, F., Picard, P., Delage, N., Tiberghien-Chatelain, F., Crosmary, M.-C., Najjar, M., Colamarino, R., et al. (2019) · Drug Design Development and Therapy · doi:10.2147/dddt.s207350 · Cited by 18 · see citing works
The role of NMDARs in the anesthetic and antidepressant effects of ketamine
Zhou, L., & Duan, J. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14464 · Cited by 17 · see citing works
Elmer, G. I., Tapocik, J. D., Mayo, C. L., Zanos, P., & Gould, T. D. (2020) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2020.172973 · Cited by 17 · see citing works
Subchronic administration of (R,S)-ketamine induces ketamine ring hydroxylation in Wistar rats
Moaddel, R., Sanghvi, M., Ramamoorthy, A., Jóźwiak, K., Singh, N., Green, C., O’Loughlin, K. G., Torjman, M. C., & Wainer, I. W. (2016) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2016.03.030 · Cited by 17 · see citing works
Self-citationAntidepressant Actions of Ketamine: Potential Role of L-Type Calcium Channels
Robinson, B. L., Gu, Q., & Kanungo, J. (2021) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.0c00411 · Cited by 16 · see citing works
Repeated, low-dose oral esketamine in patients with treatment-resistant depression: pilot study
Smith-Apeldoorn, S. Y., Veraart, J. K. E., Ruhé, H. G., Rot, M. A. H., Kamphuis, J., de Boer, M. K., & Schoevers, R. A. (2021) · BJPsych Open · doi:10.1192/bjo.2021.1059 · Cited by 16 · see citing works
Jurásek, B., Králík, F., Rimpelová, S., Čejka, J., Setnička, V., Ruml, T., Kuchař, M., & Kohout, M. (2018) · New Journal of Chemistry · doi:10.1039/c8nj03107j · Cited by 16 · see citing works
- Authors
- Moaddel, R., Abdrakhmanova, G., Kozak, J., Jozwiak, K., Toll, L., Jimenez, L., Rosenberg, A., Tran, T., Xiao, Y., Zarate, C. A., & Wainer, I. W.
- Affiliations
- National Institutes of Health (US)
- Virginia Commonwealth University (US)
- Medical University of Lublin (PL)
- Torrey Pines Institute For Molecular Studies (US)
- SRI International (US)
- Georgetown University (US)
- Corresponding author
- Wainer, Irving W.
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 698
- Issue
- 1-3
- Pages
- 228-234
- ISSN
- 0014-2999 (ISSN-L)
- PMC
- PMC3534778
- OpenAlex
- W2068032560
- Cited by
- 176
- References
- 22
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 11 · 2023: 14 · 2022: 14 · 2021: 15 · 2020: 23 · 2019: 11 · 2018: 15 · 2017: 16 · 2016: 15 · 2015: 14 · 2014: 9 · 2013: 4
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Intramural Research Programs of the National Institute of Aging (IWW)
- National Institute of Mental Health (CAZ)
- Brain & Behavior Research Foundation Bipolar Disorders Award (CAZ), NIA (N01AG-3–1009 (GA,LT,LJ))
- Foundation for Polish Science (FOCUS and TEAM Programmes) (KJ).
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Keywords
- ketamine metabolites, norketamine, dehydronorketamine, hydroxynorketamine, alpha7 nicotinic acetylcholine receptor, α3β4 nicotinic acetylcholine receptor, negative allosteric modulation, NMDA receptor binding, nicotinic antagonists
- MeSH terms
- Acetylcholine, Anesthetics, Animals, Cell Line, Dose-Response Relationship, Drug, Ketamine, Receptors, Nicotinic, Receptors, N-Methyl-D-Aspartate, Nicotinic Agonists, Rats, Electrophysiological Phenomena, alpha7 Nicotinic Acetylcholine Receptor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
