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Common Neurotransmission Recruited in (R,S)-Ketamine and (2R,6R)-Hydroxynorketamine–Induced Sustained Antidepressant-like Effects

  • Thu Ha Pham
    Affiliations
    CESP/UMR-S 1178, Université Paris-Sud, Faculté de Pharmacie, INSERM, Université Paris-Saclay, Châtenay Malabry, France
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  • Céline Defaix
    Affiliations
    CESP/UMR-S 1178, Université Paris-Sud, Faculté de Pharmacie, INSERM, Université Paris-Saclay, Châtenay Malabry, France
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  • Xiaoming Xu
    Affiliations
    Department of Medicine, Columbia University, New York, New York

    Organic Chemistry Collaborative Center, Department of Medicine, Columbia University, New York, New York
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  • Shi-Xian Deng
    Affiliations
    Department of Medicine, Columbia University, New York, New York

    Organic Chemistry Collaborative Center, Department of Medicine, Columbia University, New York, New York
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  • Nicolas Fabresse
    Affiliations
    Laboratoire de Pharmacologie-Toxicologie, Centre Hospitalier Universitaire Raymond Poincaré, AP-HP, Garches, France
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  • Jean-Claude Alvarez
    Affiliations
    Laboratoire de Pharmacologie-Toxicologie, Centre Hospitalier Universitaire Raymond Poincaré, AP-HP, Garches, France
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  • Donald W. Landry
    Affiliations
    Department of Medicine, Columbia University, New York, New York

    Organic Chemistry Collaborative Center, Department of Medicine, Columbia University, New York, New York
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  • Rebecca A. Brachman
    Affiliations
    Department of Psychiatry, Columbia University, New York, New York
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  • Author Footnotes
    1 CAD and AMG contributed equally to this work.
    Christine A. Denny
    Footnotes
    1 CAD and AMG contributed equally to this work.
    Affiliations
    Department of Psychiatry, Columbia University, New York, New York

    Division of Integrative Neuroscience, Research Foundation for Mental Hygiene, Inc/New York State Psychiatric Institute, New York, New York
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  • Author Footnotes
    1 CAD and AMG contributed equally to this work.
    Alain M. Gardier
    Correspondence
    Address correspondence to Alain M. Gardier, Pharm.D., Ph.D., Laboratoire de Neuropharmacologie, CESP/UMR-S 1178 “Depression, Plasticity and Resistance to Antidepressant Drugs,” Inserm, Univ. Paris-Sud, Fac. Pharmacie, 5 Rue J-B Clement, Tour D1, 2e etage, F-92296 Chatenay Malabry cedex, France.
    Footnotes
    1 CAD and AMG contributed equally to this work.
    Affiliations
    CESP/UMR-S 1178, Université Paris-Sud, Faculté de Pharmacie, INSERM, Université Paris-Saclay, Châtenay Malabry, France
    Search for articles by this author
  • Author Footnotes
    1 CAD and AMG contributed equally to this work.
      Racemic (R,S)-ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, exhibits a rapid and persistent antidepressant activity at subanesthetic doses in treatment-resistant depressed patients and in preclinical studies in rodents (
      • Duman R.S.
      • Aghajanian G.K.
      • Sanacora G.
      • Krystal J.H.
      Synaptic plasticity and depression: New insights from stress and rapid-acting antidepressants.
      ). (R,S)-ketamine also induces stress resilience (
      • Brachman R.A.
      • McGowan J.C.
      • Perusini J.N.
      • Lim S.C.
      • Pham T.H.
      • Faye C.
      • et al.
      Ketamine as a prophylactic against stress-induced depressive-like behavior.
      ). Molecular and cellular mechanisms mediating these activities are unknown. However, (R,S)-ketamine unlikely exerts its antidepressant-like activity solely via NMDAR blockade. We previously reported that (R,S)-ketamine-induced increases in presynaptic serotonin (5-hydroxytryptamine [5-HT]) release in the medial prefrontal cortex (mPFC) is correlated with its antidepressant-like activity in mice (
      • Pham T.H.
      • Mendez-David I.
      • Defaix C.
      • Guiard B.P.
      • Tritschler L.
      • David D.J.
      • et al.
      Ketamine treatment involves medial prefrontal cortex serotonin to induce a rapid antidepressant-like activity in BALB/cJ mice.
      ). The control exerted by the mPFC is important in regulating stress processing and in mediating antidepressant-like activity of both selective serotonin reuptake inhibitors and ketamine. However, regulation of synaptic excitatory/inhibitory balance and concomitant changes in glutamate (Glu)/gamma-aminobutyric acid (GABA) neurotransmission induced by (R,S)-ketamine in rodent mPFC are unclear (
      • Moghaddam B.
      • Adams B.
      • Verma A.
      • Daly D.
      Activation of glutamatergic neurotransmission by ketamine: A novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex.
      ).
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