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Research Articles, Neurobiology of Disease

NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine

Panos Zanos, Kyle A. Brown, Polymnia Georgiou, Peixiong Yuan, Carlos A. Zarate Jr, Scott M. Thompson and Todd D. Gould
Journal of Neuroscience 8 February 2023, 43 (6) 1038-1050; https://doi.org/10.1523/JNEUROSCI.1316-22.2022
Panos Zanos
1Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, Maryland 21201
2Department of Psychology, University of Cyprus, Nicosia 2109, Cyprus
5Department of Physiology, School of Medicine, University of Maryland, Baltimore, Maryland 21201
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Kyle A. Brown
1Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, Maryland 21201
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Polymnia Georgiou
1Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, Maryland 21201
3Department of Biology, University of Cyprus, Nicosia 2109, Cyprus
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Peixiong Yuan
4Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892
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Carlos A. Zarate Jr
4Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892
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Scott M. Thompson
1Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, Maryland 21201
5Department of Physiology, School of Medicine, University of Maryland, Baltimore, Maryland 21201
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Todd D. Gould
1Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, Maryland 21201
6Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, Maryland 21201
7Department of Anatomy & Neurobiology, School of Medicine, University of Maryland, Baltimore, Maryland 21201
8Veterans Affairs Maryland Health Care System, Baltimore, Maryland 21201
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  • Figure 1.
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    Figure 1.

    High doses of ketamine do not elicit antidepressant-relevant behavioral actions in mice. Mice received an injection of vehicle or different doses of racemic ketamine and were assessed for antidepressant-like responses 24 h later. A, Ketamine at the dose of 10 mg/kg significantly decreased escape failures in helpless mice, whereas the doses of 1, 3, 30, and 100 mg/kg did not exert significant antidepressant-relevant reductions in escape failures in the learned helplessness paradigm. B, Similarly, ketamine at the dose of 10 mg/kg reversed the decrease in sucrose preference of mice that underwent chronic social defeat stress whereas the high dose of 100 mg/kg did not elicit such an antidepressant-related response. Mice were tested for sucrose versus water preference during the 24-h period following drug administration. Data are the mean ± SEM; *p < 0.05, ***p < 0.001 as indicated by Holm–Šídák post hoc comparisons. See Table 1 for complete details on the statistical analyses and precise group sizes. CSDS, chronic social defeat stress; KET, racemic ketamine; SAL, saline; Treat, treatment.

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    Figure 2.

    Blocking NMDAR activity prevents the antidepressant-relevant behavioral effects of ketamine. A, Mice received an injection of vehicle or the NMDAR channel blocker MK-801 (0.1 mg/kg) and 10 min later they received an injection of vehicle or racemic ketamine (10 mg/kg). MK-801 pretreatment prevented the antidepressant-relevant behavioral actions of ketamine in the learned helplessness paradigm. B, Similarly, pretreatment with the competitive NMDAR blocker (±)-CPP (10 mg/kg) blocked ketamine's antidepressant-relevant actions in the learned helplessness paradigm. C, MK-801 (0.1 mg/kg) pretreatment also prevented the anti-anhedonic actions of ketamine in mice that underwent chronic social defeat stress, as measured by the sucrose preference test. D, MK-801 (0.03 mg/kg) pretreatment prevented ketamine's actions on immobility time in the forced-swim test. E, Co-administration of subeffective doses of ketamine with the NMDAR positive modulator rapastinel induced a synergistic reduction of escape failures in helpless mice in the learned helplessness paradigm. In all paradigms, mice were tested 24 h following drug administration. Data are the mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001 as indicated by Holm–Šídák post hoc comparisons. See Table 1 for complete details on the statistical analyses and precise group sizes. CSDS, chronic social defeat stress; KET, racemic ketamine; SAL, saline; Treat, treatment.

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    Figure 3.

    Blocking NMDAR activity prevents the antidepressant-relevant behavioral effects of distinct rapid-acting antidepressant compounds. A, B, Mice received an injection of vehicle or the NMDAR channel blocker MK-801 and 10 min later were given an additional injection of vehicle or ketamine's metabolite (2R,6R)-hydroxynorketamine (HNK; 10 mg/kg) and tested in the forced swim test 24 h later. While (A) the dose of 0.1 mg/kg MK-801 completely prevented the antidepressant-like behavioral actions of (2R,6R)-HNK, (B) 0.03 mg/kg MK-801 did not prevent (2R,6R)-HNK's actions to decrease immobility time in the forced-swim test. MK-801 pretreatment (0.1 mg/kg) prevented the antidepressant-relevant behavioral actions of (C) the negative allosteric modulator of GABAA receptors containing α5 subunits (GABA-NAM) MRK-016 in the forced-swim test. MK-801 pretreatment (0.1 mg/kg) prevented the antidepressant-like effects of (D) (2R,6R)-HNK, (E) MRK-016, and (F) the mGlu2/3 receptor antagonist LY341495 in the learned helplessness paradigm 24 h following drug administration. Data are the mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001 as indicated by Holm–Šídák post hoc comparisons. See Table 1 for complete details on the statistical analyses and precise group sizes. KET, racemic ketamine; SAL, saline.

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    Figure 4.

    Blocking NMDAR activity prevents the procognitive and synaptic actions of ketamine. A, Mice received an injection of vehicle or different doses of racemic ketamine and were tested for short-term novel object recognition memory 24 h after drug administration. Ketamine (10 mg/kg) enhanced the discrimination index, indicative of a procognitive effect, whereas a higher dose of ketamine (100 mg/kg) impaired object recognition memory. B, Administration of the NMDAR channel blocker MK-801 (0.1 mg/kg) 10 min before ketamine (10 mg/kg) prevented the procognitive effect of ketamine in the novel object recognition test. C, Representative western blot images for GluA1 and GluA2 AMPAR subunits from hippocampal synaptoneurosomes. D, E, Pretreatment with MK-801 prevented the ketamine-induced enhancement of synaptoneurosomal levels of GluA1 and GluA2 AMPAR subunits. F, Traces composed of representative sweeps from 5 min pre-tetanus (gray) and 56–60 min post-tetanus (black) from SAL-SAL, SAL-KET, MK-801-SAL, and MK-801-KET treatment groups. G, H, Pretreatment with MK-801 prevented the metaplastic effect of ketamine on long-term potentiation magnitude at the SC-CA1 synapse. Data are the mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001 as indicated by Holm–Šídák post hoc comparisons. See Table 1 for complete details on the statistical analyses and precise group sizes. HFS, high-frequency stimulation; KET, racemic ketamine; LTP, long-term potentiation; MK, MK-801; SAL, saline.

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    Figure 5.

    The antidepressant-like actions of ketamine are mediated through GluN2A activity. A, Mice received an injection of vehicle or the GluN2A-selective NMDAR negative allosteric modulator PEAQX (5 or 30 mg/kg) followed by an injection of vehicle or ketamine (10 mg/kg) 10 min later, and then were tested for reversal of helpless behavior 24 h later. PEAQX pretreatment, at both doses administered, prevented the antidepressant-relevant actions of ketamine to decrease escape failures of helpless mice. B, The GluN2A-selective NMDAR positive allosteric modulator GNE-5729 induced a decrease in locomotor activity of mice in the open-field test only at the highest dose administered (3 mg/kg). C, In the forced-swim test, GNE-5729 at the dose of 3 mg/kg significantly reduced immobility time of mice, indicative of an antidepressant response. D, Similarly, the dose of 1 mg/kg of GNE-5729 significantly reduced escape failures of helpless mice. Data are the mean ± SEM; *p < 0.05, ***p < 0.001 as indicated by Holm–Šídák post hoc comparisons. See Table 1 for complete details on the statistical analyses and precise group sizes. KET, ketamine; SAL, saline; VEH, vehicle.

Tables

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    Table 1.

    Statistical Analyses

    Figure/statistical testNumber of mice (as appear in graph)Factorial effectsInteraction effect
    Overall effects for Figure 1
    Factor “treatment”
    1AOne-way ANOVAn = 7, 7, 7, 6, 7, 7F(5,35) = 4.10;p = 0.005
    Factor “treatment”Factor “CSDS phase”Factor “treatment” × “CSDS phase”
    1BTwo-way RM ANOVAn = 8, 6, 7F(2,19) = 1.288;p = 0.299F(2,38) = 84.300;p < 0.0001F(4,38) = 2.737;p = 0.043
    Overall effects for Figure 2
    Factor “pretreatment”Factor “treatment”Factor “pretreatment” × “treatment”
    2ATwo-way ANOVAn = 13, 13, 13, 14F(1,48) = 3.333;p = 0.074F(1,48) = 5.134;p = 0.028F(1,48) = 1.742;p = 0.193
    2BTwo-way ANOVAn = 16, 16, 17, 17F(1,62) = 2.900;p = 0.094F(1,62) = 4.625;p = 0.035F(1,62) = 5.317;p = 0.025
    Factor “treatment” × “phase”Factor “pretreatment” × “treatment”Factor “pretreatment” × “treatment” × “phase”
    2CThree-way RM ANOVAn = 6, 6, 7, 6F(2,42) = 2.316;p = 0.111F(1,21) = 6.452;p = 0.019F(2,42) = 3.278;p = 0.048
    Factor “pretreatment”Factor “treatment”Factor “pretreatment” × “treatment”
    2DTwo-way ANOVAn = 8, 9, 9, 9F(1,31) = 4.109;p = 0.051F(1,31) = 3.230;p = 0.082F(1,31) = 7.313;p = 0.011
    Factor “co-treatment”Factor “treatment”Factor “pretreatment” × “treatment”
    2ETwo-way ANOVAn = 7, 9, 8, 8F(1,28) = 10.020;p = 0.004F(1,28) = 7.631;p = 0.010F(1,28) = 7.606;p = 0.010
    Overall effects for Figure 3
    Factor “pretreatment”Factor “treatment”Factor “pretreatment” × “treatment”
    3ATwo-way ANOVAn = 8, 9, 8, 9F(1,30) = 6.804;p = 0.014F(1,30) = 43.040;p < 0.0001F(1,30) = 6.202;p = 0.019
    3BTwo-way ANOVAn = 8, 9, 9, 9F(1,31) = 5.795;p = 0.022F(1,31) = 5.261;p = 0.029F(1,31) = 9.041;p = 0.005
    3CTwo-way ANOVAn = 8, 8, 9, 8F(1,29) = 6.209;p = 0.019F(1,29) = 3.499;p = 0.072F(1,29) = 6.077;p = 0.020
    3DTwo-way ANOVAn = 11, 8, 11, 10F(1,36) = 11.060;p = 0.002F(1,36) = 44.570;p < 0.0001F(1,36) = 19.760;p < 0.0001
    3ETwo-way ANOVAn = 8, 10, 7, 10F(1,35) = 5.753;p = 0.022F(1,35) = 6.958;p = 0.012F(1,35) = 3.737;p = 0.061
    3FTwo-way ANOVAn = 8, 7, 10, 8F(1,29) = 9.865;p = 0.004F(1,29) = 7.547;p = 0.010F(1,29) = 11.540;p = 0.002
    Overall effects for Figure 4
    Factor “treatment”
    4AOne-way ANOVAn = 8, 8, 8F(2,21) = 15.28;p < 0.0001
    Factor “pretreatment”Factor “treatment”Factor “pretreatment” × “treatment”
    4BTwo-way ANOVAn = 8, 7, 7, 8F(1,26) = 16.410;p < 0.001F(1,26) = 7.356;p = 0.012F(1,26) = 5.937;p = 0.022
    4DTwo-way ANOVAn = 10, 10, 10, 10F(1,36) = 4.468;p = 0.042F(1,36) = 1.963;p = 0.170F(1,36) = 3.944;p = 0.054
    4ETwo-way ANOVAn = 10, 10, 10, 10F(1,36) = 1.253;p = 0.270F(1,36) = 4.389;p = 0.043F(1,36) = 2.729;p = 0.107
    4HTwo-way ANOVAn = 8, 5, 5, 6F(1,20) = 11.630;p = 0.003F(1,20) = 4.616;p = 0.044F(1,20) = 6.246;p = 0.021
    Overall effects for Figure 5
    Factor “pretreatment”Factor “treatment”Factor “pretreatment” × “treatment”
    5ATwo-way ANOVAn = 6, 7, 7, 7, 7, 7F(2,35) = 1.320;p = 0.280F(1,35) = 7.287;p = 0.011F(2,35) = 4.796;p = 0.014
    Factor “treatment”
    5BOne-way ANOVAn = 6, 6, 6, 7, 7F(4,27) = 2.469;p = 0.069
    5COne-way ANOVAn = 8, 8, 8, 8, 8F(4,35) = 2.469;p = 0.088
    5DOne-way ANOVAn = 9, 8, 8, 8, 7, 8F(5,42) = 2.110;p = 0.083
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The Journal of Neuroscience: 43 (6)
Journal of Neuroscience
Vol. 43, Issue 6
8 Feb 2023
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NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine
Panos Zanos, Kyle A. Brown, Polymnia Georgiou, Peixiong Yuan, Carlos A. Zarate Jr, Scott M. Thompson, Todd D. Gould
Journal of Neuroscience 8 February 2023, 43 (6) 1038-1050; DOI: 10.1523/JNEUROSCI.1316-22.2022

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NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine
Panos Zanos, Kyle A. Brown, Polymnia Georgiou, Peixiong Yuan, Carlos A. Zarate Jr, Scott M. Thompson, Todd D. Gould
Journal of Neuroscience 8 February 2023, 43 (6) 1038-1050; DOI: 10.1523/JNEUROSCI.1316-22.2022
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Keywords

  • AMPA receptor
  • antidepressant
  • hydroxynorketamine
  • ketamine
  • LTP
  • NMDA receptor

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