| Autor: |
Chen BK; Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY, 10027, USA., Luna VM; Division of Systems Neuroscience, Research Foundation for Mental Hygiene Inc. (RFMH)/New York State Psychiatric Institute (NYSPI), New York, NY, 10032, USA.; Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), New York, NY, 10032, USA., LaGamma CT; Division of Systems Neuroscience, Research Foundation for Mental Hygiene Inc. (RFMH)/New York State Psychiatric Institute (NYSPI), New York, NY, 10032, USA.; Penn State College of Medicine, Hershey, PA, 17033, USA., Xu X; Department of Medicine, Columbia University, New York, NY, 10032, USA.; Organic Chemistry Collaborative Center (OCCC), Department of Medicine, Columbia University, New York, NY, 10032, USA., Deng SX; Department of Medicine, Columbia University, New York, NY, 10032, USA.; Organic Chemistry Collaborative Center (OCCC), Department of Medicine, Columbia University, New York, NY, 10032, USA., Suckow RF; Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), New York, NY, 10032, USA.; Nathan S. Kline Institute for Psychiatric Research (NKI), Orangeburg, NY, 10962, USA., Cooper TB; Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), New York, NY, 10032, USA.; Nathan S. Kline Institute for Psychiatric Research (NKI), Orangeburg, NY, 10962, USA., Shah A; I.I. Rabi Scholars Program, Columbia University, New York, NY, 10027, USA., Brachman RA; Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), New York, NY, 10032, USA., Mendez-David I; Université Paris-Saclay, Centre de recherche en Epidémiologie et Santé des Populations (CESP), Inserm, Faculté de Pharmacie, Châtenay-Malabry, 92290, France., David DJ; Université Paris-Saclay, Centre de recherche en Epidémiologie et Santé des Populations (CESP), Inserm, Faculté de Pharmacie, Châtenay-Malabry, 92290, France., Gardier AM; Université Paris-Saclay, Centre de recherche en Epidémiologie et Santé des Populations (CESP), Inserm, Faculté de Pharmacie, Châtenay-Malabry, 92290, France., Landry DW; Department of Medicine, Columbia University, New York, NY, 10032, USA.; Organic Chemistry Collaborative Center (OCCC), Department of Medicine, Columbia University, New York, NY, 10032, USA., Denny CA; Division of Systems Neuroscience, Research Foundation for Mental Hygiene Inc. (RFMH)/New York State Psychiatric Institute (NYSPI), New York, NY, 10032, USA. cad2125@cumc.columbia.edu.; Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), New York, NY, 10032, USA. cad2125@cumc.columbia.edu. |
| Abstrakt: |
Enhancing stress resilience in at-risk populations could significantly reduce the incidence of stress-related psychiatric disorders. We have previously reported that the administration of (R,S)-ketamine prevents stress-induced depressive-like behavior in male mice, perhaps by altering α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated transmission in hippocampal CA3. However, it is still unknown whether metabolites of (R,S)-ketamine can be prophylactic in both sexes. We administered (R,S)-ketamine or its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) and (2S,6S)-hydroxynorketamine ((2S,6S)-HNK) at various doses 1 week before one of a number of stressors in male and female 129S6/SvEv mice. Patch clamp electrophysiology was used to determine the effect of prophylactic drug administration on glutamatergic activity in CA3. To examine the interaction between ovarian hormones and stress resilience, female mice also underwent ovariectomy (OVX) surgery and a hormone replacement protocol prior to drug administration. (2S,6S)-HNK and (2R,6R)-HNK protected against distinct stress-induced behaviors in both sexes, with (2S,6S)-HNK attenuating learned fear in male mice, and (2R,6R)-HNK preventing stress-induced depressive-like behavior in both sexes. (R,S)-ketamine and (2R,6R)-HNK, but not (2S,6S)-HNK, attenuated large-amplitude AMPAR-mediated bursts in hippocampal CA3. All three compounds reduced N-methyl-D-aspartate receptor (NMDAR)-mediated currents 1 week after administration. Furthermore, ovarian-derived hormones were necessary for and sufficient to restore (R,S)-ketamine- and (2R,6R)-HNK-mediated prophylaxis in female mice. Our data provide further evidence that resilience-enhancing prophylactics may alter AMPAR-mediated glutamatergic transmission in CA3. Moreover, we show that prophylactics against stress-induced depressive-like behavior can be developed in a sex-specific manner and demonstrate that ovarian hormones are necessary for the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-HNK in female mice. |
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