PMID- 32417852
OWN - NLM
STAT- MEDLINE
DCOM- 20210623
LR  - 20210802
IS  - 1740-634X (Electronic)
IS  - 0893-133X (Print)
IS  - 0893-133X (Linking)
VI  - 45
IP  - 9
DP  - 2020 Aug
TI  - Sex-specific neurobiological actions of prophylactic (R,S)-ketamine, 
      (2R,6R)-hydroxynorketamine, and (2S,6S)-hydroxynorketamine.
PG  - 1545-1556
LID - 10.1038/s41386-020-0714-z [doi]
AB  - 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 
      alpha-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.
FAU - Chen, Briana K
AU  - Chen BK
AUID- ORCID: 0000-0003-1982-1389
AD  - Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY, 
      10027, USA.
FAU - Luna, Victor M
AU  - Luna VM
AD  - Division of Systems Neuroscience, Research Foundation for Mental Hygiene Inc. 
      (RFMH)/New York State Psychiatric Institute (NYSPI), New York, NY, 10032, USA.
AD  - Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), New 
      York, NY, 10032, USA.
FAU - LaGamma, Christina T
AU  - LaGamma CT
AD  - Division of Systems Neuroscience, Research Foundation for Mental Hygiene Inc. 
      (RFMH)/New York State Psychiatric Institute (NYSPI), New York, NY, 10032, USA.
AD  - Penn State College of Medicine, Hershey, PA, 17033, USA.
FAU - Xu, Xiaoming
AU  - Xu X
AD  - Department of Medicine, Columbia University, New York, NY, 10032, USA.
AD  - Organic Chemistry Collaborative Center (OCCC), Department of Medicine, Columbia 
      University, New York, NY, 10032, USA.
FAU - Deng, Shi-Xian
AU  - Deng SX
AD  - Department of Medicine, Columbia University, New York, NY, 10032, USA.
AD  - Organic Chemistry Collaborative Center (OCCC), Department of Medicine, Columbia 
      University, New York, NY, 10032, USA.
FAU - Suckow, Raymond F
AU  - Suckow RF
AD  - Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), New 
      York, NY, 10032, USA.
AD  - Nathan S. Kline Institute for Psychiatric Research (NKI), Orangeburg, NY, 10962, 
      USA.
FAU - Cooper, Thomas B
AU  - Cooper TB
AD  - Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), New 
      York, NY, 10032, USA.
AD  - Nathan S. Kline Institute for Psychiatric Research (NKI), Orangeburg, NY, 10962, 
      USA.
FAU - Shah, Abhishek
AU  - Shah A
AUID- ORCID: 0000-0001-9643-4564
AD  - I.I. Rabi Scholars Program, Columbia University, New York, NY, 10027, USA.
FAU - Brachman, Rebecca A
AU  - Brachman RA
AD  - Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), New 
      York, NY, 10032, USA.
FAU - Mendez-David, Indira
AU  - Mendez-David I
AD  - Universite Paris-Saclay, Centre de recherche en Epidemiologie et Sante des 
      Populations (CESP), Inserm, Faculte de Pharmacie, Chatenay-Malabry, 92290, 
      France.
FAU - David, Denis J
AU  - David DJ
AD  - Universite Paris-Saclay, Centre de recherche en Epidemiologie et Sante des 
      Populations (CESP), Inserm, Faculte de Pharmacie, Chatenay-Malabry, 92290, 
      France.
FAU - Gardier, Alain M
AU  - Gardier AM
AD  - Universite Paris-Saclay, Centre de recherche en Epidemiologie et Sante des 
      Populations (CESP), Inserm, Faculte de Pharmacie, Chatenay-Malabry, 92290, 
      France.
FAU - Landry, Donald W
AU  - Landry DW
AD  - Department of Medicine, Columbia University, New York, NY, 10032, USA.
AD  - Organic Chemistry Collaborative Center (OCCC), Department of Medicine, Columbia 
      University, New York, NY, 10032, USA.
FAU - Denny, Christine A
AU  - Denny CA
AUID- ORCID: 0000-0002-6926-2020
AD  - 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.
AD  - Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), New 
      York, NY, 10032, USA. cad2125@cumc.columbia.edu.
LA  - eng
GR  - K01 AG054765/AG/NIA NIH HHS/United States
GR  - DP5 OD017908/CD/ODCDC CDC HHS/United States
GR  - DP5 OD017908/OD/NIH HHS/United States
GR  - R21 NS114870/NS/NINDS NIH HHS/United States
GR  - F31 MH121023/MH/NIMH NIH HHS/United States
GR  - T32 HD007430-19/U.S. Department of Health & Human Services | National 
      Institutes of Health (NIH)/International
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20200517
PL  - England
TA  - Neuropsychopharmacology
JT  - Neuropsychopharmacology : official publication of the American College of 
      Neuropsychopharmacology
JID - 8904907
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 690G0D6V8H (Ketamine)
RN  - 81395-70-2 (6-hydroxynorketamine)
SB  - IM
MH  - Animals
MH  - Electrophysiological Phenomena
MH  - Female
MH  - Hippocampus/metabolism
MH  - *Ketamine/analogs & derivatives/pharmacology
MH  - Male
MH  - Mice
MH  - Receptors, N-Methyl-D-Aspartate/metabolism
PMC - PMC7360766
EDAT- 2020/05/18 06:00
MHDA- 2021/06/24 06:00
PMCR- 2021/08/01
CRDT- 2020/05/18 06:00
PHST- 2020/02/25 00:00 [received]
PHST- 2020/05/11 00:00 [accepted]
PHST- 2020/05/08 00:00 [revised]
PHST- 2020/05/18 06:00 [pubmed]
PHST- 2021/06/24 06:00 [medline]
PHST- 2020/05/18 06:00 [entrez]
PHST- 2021/08/01 00:00 [pmc-release]
AID - 10.1038/s41386-020-0714-z [pii]
AID - 714 [pii]
AID - 10.1038/s41386-020-0714-z [doi]
PST - ppublish
SO  - Neuropsychopharmacology. 2020 Aug;45(9):1545-1556. doi: 
      10.1038/s41386-020-0714-z. Epub 2020 May 17.