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Review ArticleReview Article

Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications

Jaclyn N. Highland, Panos Zanos, Lace M. Riggs, Polymnia Georgiou, Sarah M. Clark, Patrick J. Morris, Ruin Moaddel, Craig J. Thomas, Carlos A. Zarate Jr., Edna F. R. Pereira and Todd D. Gould
Robert Dantzer, ASSOCIATE EDITOR
Pharmacological Reviews April 2021, 73 (2) 763-791; DOI: https://doi.org/10.1124/pharmrev.120.000149
Jaclyn N. Highland
Departments of Psychiatry (J.N.H., P.Z., L.M.R., P.G., S.M.C., T.D.G.), Pharmacology (P.Z., T.D.G.), Physiology (P.Z.), Anatomy and Neurobiology (T.D.G), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P.), Programs in Toxicology (J.N.H.) and Neuroscience (L.M.R.), and Veterans Affairs Maryland Health Care System, University of Maryland School of Medicine, Baltimore, Maryland (T.D.G.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Panos Zanos
Departments of Psychiatry (J.N.H., P.Z., L.M.R., P.G., S.M.C., T.D.G.), Pharmacology (P.Z., T.D.G.), Physiology (P.Z.), Anatomy and Neurobiology (T.D.G), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P.), Programs in Toxicology (J.N.H.) and Neuroscience (L.M.R.), and Veterans Affairs Maryland Health Care System, University of Maryland School of Medicine, Baltimore, Maryland (T.D.G.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Lace M. Riggs
Departments of Psychiatry (J.N.H., P.Z., L.M.R., P.G., S.M.C., T.D.G.), Pharmacology (P.Z., T.D.G.), Physiology (P.Z.), Anatomy and Neurobiology (T.D.G), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P.), Programs in Toxicology (J.N.H.) and Neuroscience (L.M.R.), and Veterans Affairs Maryland Health Care System, University of Maryland School of Medicine, Baltimore, Maryland (T.D.G.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Polymnia Georgiou
Departments of Psychiatry (J.N.H., P.Z., L.M.R., P.G., S.M.C., T.D.G.), Pharmacology (P.Z., T.D.G.), Physiology (P.Z.), Anatomy and Neurobiology (T.D.G), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P.), Programs in Toxicology (J.N.H.) and Neuroscience (L.M.R.), and Veterans Affairs Maryland Health Care System, University of Maryland School of Medicine, Baltimore, Maryland (T.D.G.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Sarah M. Clark
Departments of Psychiatry (J.N.H., P.Z., L.M.R., P.G., S.M.C., T.D.G.), Pharmacology (P.Z., T.D.G.), Physiology (P.Z.), Anatomy and Neurobiology (T.D.G), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P.), Programs in Toxicology (J.N.H.) and Neuroscience (L.M.R.), and Veterans Affairs Maryland Health Care System, University of Maryland School of Medicine, Baltimore, Maryland (T.D.G.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Patrick J. Morris
Departments of Psychiatry (J.N.H., P.Z., L.M.R., P.G., S.M.C., T.D.G.), Pharmacology (P.Z., T.D.G.), Physiology (P.Z.), Anatomy and Neurobiology (T.D.G), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P.), Programs in Toxicology (J.N.H.) and Neuroscience (L.M.R.), and Veterans Affairs Maryland Health Care System, University of Maryland School of Medicine, Baltimore, Maryland (T.D.G.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Ruin Moaddel
Departments of Psychiatry (J.N.H., P.Z., L.M.R., P.G., S.M.C., T.D.G.), Pharmacology (P.Z., T.D.G.), Physiology (P.Z.), Anatomy and Neurobiology (T.D.G), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P.), Programs in Toxicology (J.N.H.) and Neuroscience (L.M.R.), and Veterans Affairs Maryland Health Care System, University of Maryland School of Medicine, Baltimore, Maryland (T.D.G.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Craig J. Thomas
Departments of Psychiatry (J.N.H., P.Z., L.M.R., P.G., S.M.C., T.D.G.), Pharmacology (P.Z., T.D.G.), Physiology (P.Z.), Anatomy and Neurobiology (T.D.G), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P.), Programs in Toxicology (J.N.H.) and Neuroscience (L.M.R.), and Veterans Affairs Maryland Health Care System, University of Maryland School of Medicine, Baltimore, Maryland (T.D.G.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Carlos A. Zarate Jr.
Departments of Psychiatry (J.N.H., P.Z., L.M.R., P.G., S.M.C., T.D.G.), Pharmacology (P.Z., T.D.G.), Physiology (P.Z.), Anatomy and Neurobiology (T.D.G), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P.), Programs in Toxicology (J.N.H.) and Neuroscience (L.M.R.), and Veterans Affairs Maryland Health Care System, University of Maryland School of Medicine, Baltimore, Maryland (T.D.G.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Edna F. R. Pereira
Departments of Psychiatry (J.N.H., P.Z., L.M.R., P.G., S.M.C., T.D.G.), Pharmacology (P.Z., T.D.G.), Physiology (P.Z.), Anatomy and Neurobiology (T.D.G), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P.), Programs in Toxicology (J.N.H.) and Neuroscience (L.M.R.), and Veterans Affairs Maryland Health Care System, University of Maryland School of Medicine, Baltimore, Maryland (T.D.G.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Todd D. Gould
Departments of Psychiatry (J.N.H., P.Z., L.M.R., P.G., S.M.C., T.D.G.), Pharmacology (P.Z., T.D.G.), Physiology (P.Z.), Anatomy and Neurobiology (T.D.G), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P.), Programs in Toxicology (J.N.H.) and Neuroscience (L.M.R.), and Veterans Affairs Maryland Health Care System, University of Maryland School of Medicine, Baltimore, Maryland (T.D.G.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Robert Dantzer
Roles: ASSOCIATE EDITOR
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  • Fig. 1.
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    Fig. 1.

    Metabolic formation of hydroxynorketamines from ketamine. (R,S)-ketamine (KET) is N-demethylated to form (R,S)-norketamine (norKET), which is then further metabolized to form the HNKs and dehydronorketamine (DHNK). Via this pathway, (R,S)-norKET is hydroxylated to form the HNKs as shown [see Portmann et al. (2010); Desta et al. (2012)]. Ketamine additionally undergoes direct hydroxylation to form the 6-hydroxyketamines (HKs), which are then N-demethylated to form the (2,6)-HNKs (Portmann et al., 2010; Desta et al., 2012).

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    Fig. 2.

    Putative synaptic mechanisms of (2R,6R)- and (2S,6S)-hydroxynorketamine. (2R,6R)- HNK acts on the presynaptic terminal to increase glutamate release, possibly via signaling mechanisms convergent with mGlu2, whereby (2R,6R)-HNK disinhibits the mGlu2-induced cAMP release, or via another glutamate release mechanism. Subsequent to enhanced glutamate release, AMPAR activation leads to enhanced BDNF release, TrkB activation, and subsequent activation of plasticity-relevant signal cascades, including an increase in protein kinase B (AKT), extracellular signal–related kinases (ERK)/mitogen-activated proteain kinases (MAPK), and mTORC1 pathway activity. These signaling cascades result in protein synthesis, including increased AMPAR expression, and synaptogenesis, ultimately promoting enhanced synaptic strength. (2R,6R)-HNK may also disrupt TrkB/AP-2 interactions, thereby inhibiting TrkB endocytosis and enhancing TrkB stability at the synapse. Additionally, (2S,6S)-HNK has moderate affinity to inhibit NMDARs and may act to increase intracellular signal cascades via an NMDAR inhibition–dependent pathway, including inhibition of eEF2 signaling in addition to increased AKT, ERK/MAPK, and mTORC1 signaling.

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    TABLE 1

    CNS concentrations of (2R,6R)-HNK relevant to antidepressant actions

    SpeciesExperimental DetailsConcentration
    After ketamine dosing
     HumansEstimated peak unbound brain concentration after a typical antidepressant treatment (0.5 mg/kg, i.v., over 40 min)≤37.8 ± 14.3 nMa,b,c
     MicePeak total (bound and unbound) brain concentrations after a dose (10 mg/kg, i.p.) frequently reported to induce relevant behavioral actions1.54–2.46 µmol/kgb,d,e
    After (2R,6R)-HNK dosing
     MicePeak total concentrations after a dose (10 mg/kg, i.p.) frequently reported to induce relevant behavioral actions measured in:
    a) Whole brain10.66–17.80 µmol/kgd,f,g,h
    b) CSF18.40 µMg
    c) Extracellular hippocampal space7.57 ± 2.13 µMh
    • ↵a Peak unbound brain concentrations were estimated based upon peak plasma levels 157 ± 59.2 nM.

    • ↵b Concentrations correspond to racemic mixture of (2R,6R;2S,6S)-HNK.

    • ↵c Shaffer et al. (2019).

    • ↵d Zanos et al. (2016).

    • ↵e Zanos et al. (2019a).

    • ↵f Pham et al. (2018).

    • ↵g Yamaguchi et al. (2018).

    • ↵h Lumsden et al. (2019).

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    TABLE 2

    NMDAR ligand binding and functional inhibition

    Ketamine Ki and IC50 values are only reported from studies that compared the effects of ketamine to HNKs under similar experimental conditions.

    CompoundAffinity/PotencyReferences
    NMDAR binding affinity (MK-801 displacement)
     (R,S)-ketamineKi = 0.25–1.06 µMMoaddel et al. (2013); Morris et al. (2017)
     (2S,6S)-HNKKi = 7.34–21.19 µM
     (2R,6R)-HNKKi > 100 µM
     (2R,5R)-HNKKi > 100 µM
     (2S,5S)-HNKKi > 100 µM
     (2R,5S)-HNKKi > 100 µM
     (2S,5R)-HNKKi > 100 µM
     (2R,4R)-HNKKi > 100 µM
     (2S,4S)-HNKKi > 100 µM
     (2R,4S)-HNKKi > 100 µM
     (2S,4R)-HNKKi > 100 µM
     (2R,6R)-HNKKi > 10 µMZanos et al. (2016)
     (2S,6S)-HNKKi > 10 µM
    Inhibition of NMDAR-mediated current amplitude, X. laevis oocytes
     GluN subunits1A/2A1A/2B1A/2C1A/2D
     (R,S)-ketamineIC50 = 3.3 µMIC50 = 0.9 µMIC50 = 1.7 µMIC50 = 2.4 µMDravid et al. (2007); Lumsden et al. (2019)
     (2R,6R)-HNKIC50 = 498 µMIC50 = 258 µMIC50 = 202 µMIC50 = 287 µM
     (2S,6S)-HNKIC50 = 43 µMIC50 = 21 µMIC50 = 15 µM13 µM
    Inhibition of NMDAR-mediated current amplitude, HEK-293 cells
     GluN subunits1A/2A1A/2B
     (R,S)-ketamineIC50 = 0.8 µM at pH 6.8NDAbbott and Popescu (2020)
    IC50 = 0.5 µM at pH 7.2
     (2R,6R)-HNKIC50 = 46 µM at pH 6.8IC50 = 39 µM at pH 6.8
    IC50 = 46 µM at pH 7.2IC50 = 69 µM at pH 7.2
    Inhibition of NMDAR-mediated fEPSP slope, SC-CA1 mouse hippocampal slices
     (R,S)-ketamineIC50 = 4.5 µMLumsden et al. (2019)
     (2R,6R)-HNKIC50 = 211.9 µM
     (2S,6S)-HNKIC50 = 47.2 µM
    Inhibition of NMDAR-mediated mEPSC amplitude, CA1 neurons in rat hippocampal slices
     (R,S)-ketamineIC50 = 6.4 µMLumsden et al. (2019)
     (2R,6R)-HNKIC50 = 63.7 µM
    Inhibition of NMDAR-mediated mEPSCs, primary mouse hippocampal neurons
     (R,S)-ketamine50 µM (∼90% inhibition)Suzuki et al. (2017)
     (2R,6R)-HNK50 µM (∼40% inhibition)
    10 µM (no inhibition)
    Inhibition of NMDA-induced whole-cell current charge
     (R,S)-ketamineIC50 = 45.9 µMLumsden et al. (2019)
     (2R,6R)-HNKIC50 > 1000 µM
     (2S,6S)-HNKIC50 > 1000 µM
    Attenuation of NMDA-induced lethality in mice
     (R,S)-ketamineED50 = 6.4 mg/kg, i.p.Lumsden et al. (2019)
     (2R,6R)-HNKED50 = 227.8 mg/kg, i.p.
     (2S,6S)-HNKED50 = 18.6 mg/kg, i.p.
    • ND, not determined; SC-CA1, Schaffer collateral-CA1 hippocampal synapse.

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    TABLE 3

    Effects on synaptic glutamatergic transmission

    Contained in this table are synaptic effects other than direct effects on NMDAR function, which are shown in Table 2. Studies and experiments that did not identify an effect are not summarized in this table; please refer to the text for these details.

    Concentration/DoseTimingEffectSystemReferences
    In vitro or ex vivo application
    (2R,6R)-HNK
     0.3–30 µM (EC50 = 3.3 µM)1-h exposureIncreased fEPSP slopeaSC-CA1, rat hippocampal slicesRiggs et al. (2019)
     10 µM1-h exposureZanos et al. (2016)
     0.3–30 µM (IC50 = 3.8 µM)1-h exposureDecreased paired-pulse ratioRiggs et al. (2019)
     10 µM20-min exposureIncreased sEPSC frequency and amplitudeRat CA1 stratum radiatum interneuronsZanos et al. (2016)
     10 µM15- to 25-min exposureIncreased mEPSC frequency (no change in amplitude)Rat CA1 pyramidal neuronsRiggs et al. (2019)
     10 µM15-min exposureIncreased mEPSC frequency and amplitudeRat ventrolateral periaqueductal gray neuronsChou et al. (2018); Ye et al. (2019)
     10 µM1- to 17-min exposureNo change in AMPA-evoked currentsRat primary cortical neuronsShaffer et al. (2019)
     10 µM20-min exposureNo change in sEPSC frequency or amplitudeMouse CA1 interneurons
     3–30 µM (EC50 = 7.8 µM)2-h exposureNo change in baseline fEPSP SlopeSC-CA1, hippocampal slices from 14-day-old mouseKang et al. (2020)
    Decreased LTP
    (2S,6S)-HNK
     10 µM20-min exposureNo change in sEPSC frequency or amplitudeRat CA1 interneuronsZanos et al. (2016)
     10 µM1- to 17-min exposureNo change in AMPA-evoked currentsRat primary cortical neuronsShaffer et al. (2019)
     1–10 µM (EC50 = 1.0 µM)2-h exposureNo change in baseline fEPSP SlopeSC-CA1, hippocampal slices from 14-day-old mouseKang et al. (2020)
    Decreased LTP
    Racemic (2R,6R;2S,6S)-HNK
     20 µM30-min exposureNo change in fEPSP slopeSC-CA1, rat hippocampal slicesMichaelsson et al. (2019)
    In vivo administration
     10 mg/kg, i.p.24 h post-treatmentIncreased glutamate releaseMouse prefrontal cortex, microdialysisPham et al. (2018)
     1 nmol/side bilateral intracortical infusion24 h post-treatment
     0.075 mg/kg, i.p.1 wk post-treatmentAttenuation of AMPAR-mediated EPSC burstsMouse hippocampal pyramidal neuronsChen et al. (2020)
     5 mg/kg, i.p.3.5 h or 1 day post-treatmentIncreased magnitude of and slowed decay of LTPSC-CA1, Wistar-Kyoto stress-susceptible rats, in vivo electrophysiologyAleksandrova et al. (2020)
     10 mg/kg, i.p.24 h post-treatmentReversed stress-induced increases in paired-pulse ratiosRat ventrolateral periaqueductal gray neuronsChou et al. (2018)
    Reversed stress-induced decreased in inward AMPAR-mediated currents
    Reversed stress-induced decreases in AMPA-evoked currents
    Reversed stress-induced decreases in mEPSC frequency and amplitude
     10 mg/kg, i.p.24 h post-treatmentIncreased mEPSC frequency and amplitudeRat ventrolateral periaqueductal gray neuronsYe et al. (2019)
    Decreased paired-pulse ratio
    Increased stimulus response relationship
    Increased AMPA-evoked currents
     10 mg/kg, i.p.24 h post-treatmentDecreased mEPSC frequency and amplitudeMouse dopaminergic ventral tegmental neuronsYao et al. (2018)
    Decreased AMPAR:NDMAR ratio
    No change in firing frequency
     10 mg/kg, i.p.24 h post-treatmentDecreased LTPMouse nucleus accumbens coreYao et al. (2018)
    No change in stimulus response relation or paired-pulse ratio
     30 mg/kg, i.p.24 h post-treatmentIncreased serotonin and hypocretin-evoked sEPSC frequency and amplitudeMouse prefrontal cortex neuronsFukumoto et al. (2019)
    • SC-CA1, Schaffer collateral-CA1 hippocampal synapse; sEPSC, spontaneous excitatory postsynaptic current.

    • ↵a Shaffer et al. (2019) reported no change in SC-CA1 fEPSP slope after a 1-h exposure to 10 µM (2R,6R)-HNK.

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    TABLE 4

    Biochemical effects implicating glutamatergic neurotransmission

    Studies and experiments that did not identify an effect are not summarized in this table; please refer to the text for these details.

    CompoundConcentration/DoseTimingEffectSystemReferences
    BDNF
      (2R,6R)-HNK10 mg/kg, i.p.24 h post-treatmentIncreased BDNF protein levelsMouse hippocampusZanos et al. (2016)
    10 mg/kg, i.p.30 min post-treatmentIncreased BDNF protein levelsMouse hippocampusLumsden et al. (2019)
    10 and 50 nM1-h exposureIncreased BDNF releaseRat primary neuronsFukumoto et al. (2019)
    10–100 µM15-min exposureDecreased TrkB/AP-2 interactionsMG87:TRKB cellsFred et al. (2019)
      (2S,6S)-HNK10 mg/kg, i.p.30–60 min post-treatmentIncreased extracellular BDNF levelsMouse prefrontal cortexAnderzhanova et al. (2020)
    cAMP
      (2R,6R)-HNK10 µM15-min exposureIncreased cAMP accumulationC6 cellsWray et al. (2019)
    eEF2
      (2R,6R)-HNK10 mg/kg, i.p.1 h post-treatmentDecreased eEF2 phosphorylationMouse hippocampusZanos et al. (2016)
    24 h post-treatment
    50 µM30-min exposureDecreased eEF2 phosphorylationMouse primary neuronsSuzuki et al. (2017)
    mTOR and downstream pathways
      (2R,6R)-HNK10 mg/kg, i.p.30 min post-treatmentIncreased p-mTORMouse hippocampusLumsden et al. (2019)
    30 mg/kg, i.p.30 min post-treatmentIncreased p-mTORMouse prefrontal cortexFukumoto et al. (2019)
    1–50 nM1-h exposureIncreased pERKRat primary neuronsFukumoto et al. (2019)
      (2S,6S)-HNK20 mg/kg, i.v.20 min post-treatmentIncreased p-mTORRat prefrontal cortexPaul et al. (2014)
    0.01–1 nM1-h exposurePC-12 cells
    20 mg/kg, i.v.20–60 min post-treatmentIncreased p4E-BP1Rat prefrontal cortexPaul et al. (2014)
    Increased pp70S6K
    0.5 nM1-h exposureIncreased p4E-BP1PC-12 cellsPaul et al. (2014)
    0.5–1 nM1-h exposureIncreased pERK
    0.1–1 nM1-h exposureIncreased pAkt
    • pAkt, phosphorylated protein kinase B; p-MTOR, phosphorylated mTOR; pp70S6K, phosphorylated p70S6 kinase; p4E-BP1, phosphorylated eukaryotic initiation factor 4E-binding protein 1.

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    TABLE 5

    Changes in AMPAR expression

    Studies and experiments that did not identify an effect are not summarized in this table; please refer to the text for these details.

    CompoundEffective Dose/ConcentrationTimingEffectSystemReferences
    (2R,6R)-HNK10 mg/kg, i.p.24 h post-treatmentIncreased GluA1 protein expressionMouse hippocampusZanos et al. (2016)
    Increased GluA2 protein expression
    1–10 µM90-min exposureIncreased GluA1 surface protein expressionRat primary neuronsShaffer et al., (2019)
    0.1–10 µM180-min exposure
    200–400 nM24-h exposureIncreased GluA1 mRNA expressionU251-MG human glioblastoma cellsHo et al. (2018)
    400 nMIncreased GluA2 mRNA expression
    400 nMIncreased GluA4 mRNA expression
    400 nM24-h exposureIncreased GluA4 mRNA expressionHuman iPSC-derived astrocytesHo et al. (2018)
    (2S,6S)-HNK200–400 nM24-h exposureIncreased GluA1 mRNA expressionU251-MG human glioblastoma cellsHo et al. (2018)
    400 nMIncreased GluA2 mRNA expression
    400 nMIncreased GluA4 mRNA expression
    400 nM24-h exposureIncreased GluA1 mRNA expressionHuman iPSC-derived astrocytesHo et al. (2018)
    400 nMIncreased GluA2 mRNA expression
    400 nMIncreased GluA4 mRNA expression
    • View popup
    TABLE 6

    Effects of (2R,6R)-HNK on cellular morphology

    Subeffective or ineffective concentrations or doses are not included in this summary table. Please refer to the text for full details.

    ConcentrationTimingEffectSystemReferences
    0.5 µM3 days after 1- to 6-h drug exposureIncreased dendrite lengthMouse primary mesencephalic dopaminergic neuronsCavalleri et al. (2018)
    Increased dendrite number
    Increased soma area
    0.5 µM3 days after 1- to 6-h drug exposureIncreased dendrite lengthHuman iPSC-derived dopaminergic neuronsCavalleri et al. (2018); Collo et al., (2018)
    Increased dendrite number
    Increased size of dopaminergic bodies
    • View popup
    TABLE 7

    Example behavioral tests predictive of antidepressant effectiveness

    Behavioral TestOutcome Predictive of Antidepressant Effectiveness
    Forced swimDecreased immobility time (increased swimming)
    Learned helplessnessDecreased escape failures/reversal of escape deficits
    Novelty-suppressed feedingReduced latency to eat
    Sucrose preferenceReversal of sucrose consumption preference deficits, or increased preference (vs. water)
    Female urine sniffing preferenceReversal of preference deficits, or increased preference (vs. water or male urine)
    Social preferenceReversal of social preference deficits
    • View popup
    TABLE 8

    Preclinical behavioral effects

    Subeffective doses and studies that did not identify an effect are not summarized in this table; please refer to the text (section IV.A.1.b. Direct antidepressant-relevant effects of hydroxynorketamines) for these details.

    Behavior or TestTime Post-TreatmentEffective DosesSpeciesReferences
    Antidepressant-relevant effects
    (2R,6R)-HNK
     Forced swim test1 h5–125 mg/kg, i.p.; 15–150 mg/kg, by mouthMouseZanos et al. (2016, 2019b); Highland et al. (2019); Lumsden et al., (2019); Aguilar-Valles et al. (2020)
    3.62–36.2 pmol/side, intra-vlPAGRatChou et al. (2018)
    24 h5–125 mg/kg, i.p.; 15–150 mg/kg, by mouth; 0.036–1 nmol/side, intra-PFCMouseZanos et al. (2016, 2019b); Highland et al. (2019); Pham et al. (2018); Fukumoto et al. (2019); Lumsden et al. (2019); Chen et al. (2020)
    10 mg/kg, i.p.; 3.62 pmol/side, intra-vlPAGRatChou et al. (2018)
    3 days10 mg/kg, i.p.MouseZanos et al. (2016)
    10 mg/kg, i.p.; 3.62 pmol/side, intra-vlPAGRatChou et al. (2018)
    5 days30 mg/kg, i.p.MouseFukumoto et al. (2019)
    7 days10 mg/kg, i.p.; 3.62 pmol/side, intra-vlPAGRatChou et al. (2018)
    14 days0.025–0.075 mg/kg, i.p.MouseChen et al., (2020)
    21 days10 mg/kg, i.p.; 3.62 pmol/side, intra-vlPAGRatChou et al., (2018)
     Learned helplessness test24 h5–75 mg/kg, i.p.; 50–150 mg/kg, by mouth; 3–10 nmol/side, i.c.v.MouseZanos et al. (2016); Highland et al. (2019); Zanos et al. (2019a)
    5 days10 nmol/side, i.c.v.MouseZanos et al. (2019a)
     Adolescent exposure to live predator prior to learned helplessness test24 h20 mg/kg, i.p.MouseElmer et al. (2020)
     Novelty-suppressed feeding test30 min10 mg/kg, i.p.MouseLumsden et al. (2019)
    1 h10–20 mg/kg, i.p.MouseZanos et al. (2016); Aguilar-Valles et al. (2020)
    3 days30 mg/kg, i.p.; 3.62 pmol/side, intra-PFCMouseFukumoto et al. (2019)
     Chronic CORT–induced sucrose preference deficits24 h10 mg/kg, i.p.MouseZanos et al. (2016)
     Chronic CORT–induced female urine preference deficits24 h10 mg/kg, i.p.MouseZanos et al. (2016)
     Female urine preference24 h30 mg/kg, i.p.MouseFukumoto et al. (2019)
     CSDS-induced sucrose preference deficits24 h10 mg/kg, i.p.MouseZanos et al. (2019b)
     CSDS-induced social interaction deficits24 h20 mg/kg, i.p.MouseZanos et al. (2016)
     Footshock stress–induced sucrose preference1 h10 mg/kg, i.p.; 3.62 pmol/side, intra-vlPAGRatChou et al. (2018)
    24 h
    3 days
    7 days
    21 days
    2 days3–30 nmol/side, i.c.v.MouseZanos et al. (2019a)
     IBD-induced sucrose preference deficits1 h1 pg/side, intra-vlPAGMouseKo et al. (2020)
     Tail suspension test (in IBD model)1 h1 pg/side, intra-vlPAGMouseKo et al. (2020)
    (2S,6S)-HNK
     Forced swim test1 h25 mg/kg, i.p.MouseZanos et al. (2016)
    24 h25 mg/kg, i.p.MouseZanos et al. (2016)
     Learned helplessness test24 h75 mg/kg, i.p.MouseZanos et al. (2016)
     Forced swim test (after chronic CORT)30 min20 mg/kg, i.p.MouseYokoyama et al. (2020)
     Chronic CORT–induced sucrose preference deficits30 min20 mg/kg, i.pMouseYokoyama et al. (2020)
     Attenuation of learned fear14 days0.025–30 mg/kg, i.p.MouseaChen et al. (2020)
    Analgesic effects
    (2R,6R)-HNK
     Elevated von Frey threshold24 h10 mg/kg, i.p.MouseKroin et al. (2019)
     Reduced mechanical allodynia in CRPS1 model0–4 days10 mg/kg/day × 10 3 days, i.p.MouseKroin et al. (2019)
     Reduced mechanical allodynia in postoperative pain model0–5 days10 mg/kg/day × 10 3 days, i.p.MouseKroin et al. (2019)
    Aggression and social dominance
    (2R,6R)-HNK
     Enhanced aggression1 h10 mg/kg, i.p.; 1–10 pg/side, intra-vlPAGRatChou (2020)
    24 h10 mg/kg, i.p.; 1–10 pg/side, intra-vlPAGRatYe et al. (2019); Chou (2020)
    3 days10 mg/kg, i.p.; 10 pg/side, intra-vlPAGRatYe et al. (2019)
    7 days
    14 days
    21 days
    28 days
     Enhanced social dominance24 h10 mg/kg, i.p.RatYe et al. (2019)
    • CORT, corticosterone; CSDS, chronic social defeat stress; IBD, inflammatory bowel disease; vlPAG, ventrolateral periaqueductal gray.

    • ↵a Effect observed only in female, but not male, mice.

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Pharmacological Reviews: 73 (2)
Pharmacological Reviews
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1 Apr 2021
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Hydroxynorketamines Pharmacology

Jaclyn N. Highland, Panos Zanos, Lace M. Riggs, Polymnia Georgiou, Sarah M. Clark, Patrick J. Morris, Ruin Moaddel, Craig J. Thomas, Carlos A. Zarate, Edna F. R. Pereira and Todd D. Gould
Pharmacological Reviews April 1, 2021, 73 (2) 763-791; DOI: https://doi.org/10.1124/pharmrev.120.000149

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Review ArticleReview Article

Hydroxynorketamines Pharmacology

Jaclyn N. Highland, Panos Zanos, Lace M. Riggs, Polymnia Georgiou, Sarah M. Clark, Patrick J. Morris, Ruin Moaddel, Craig J. Thomas, Carlos A. Zarate, Edna F. R. Pereira and Todd D. Gould
Pharmacological Reviews April 1, 2021, 73 (2) 763-791; DOI: https://doi.org/10.1124/pharmrev.120.000149
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