Sex-specific neurobiological actions of prophylactic (R,S)-ketamine, (2R,6R)-hydroxynorketamine, and (2S,6S)-hydroxynorketamine

被引:44
|
作者
Chen, Briana K. [1 ]
Luna, Victor M. [2 ,3 ]
LaGamma, Christina T. [2 ,9 ]
Xu, Xiaoming [4 ,5 ]
Deng, Shi-Xian [4 ,5 ]
Suckow, Raymond F. [3 ,6 ]
Cooper, Thomas B. [3 ,6 ]
Shah, Abhishek [7 ]
Brachman, Rebecca A. [3 ]
Mendez-David, Indira [8 ]
David, Denis J. [8 ]
Gardier, Alain M. [8 ]
Landry, Donald W. [4 ,5 ]
Denny, Christine A. [2 ,3 ]
机构
[1] Columbia Univ, Doctoral Program Neurobiol & Behav, New York, NY 10027 USA
[2] Neurosci Res Fdn Mental Hyg Inc, Div Syst Neurosci, RFMH New York State Psychiat Inst NYSPI, New York, NY 10032 USA
[3] Columbia Univ, Dept Psychiat, Irving Med Ctr CUIMC, New York, NY 10032 USA
[4] Columbia Univ, Dept Med, New York, NY 10032 USA
[5] Columbia Univ, Organ Chem Collaborat Ctr OCCC, Dept Med, New York, NY 10032 USA
[6] Nathan S Kline Inst Psychiat Res NKI, Orangeburg, NY 10962 USA
[7] Columbia Univ, Ij Rabi Scholars Program, New York, NY 10027 USA
[8] Univ Paris Saclay, Ctr Rech Epidemiol & Sante Populat, INSERM, Fac Pharm, F-92290 Chatenay Malabry, France
[9] Penn State Coll Med, Hershey, PA 17033 USA
关键词
TREATMENT-RESISTANT DEPRESSION; POSTTRAUMATIC-STRESS-DISORDER; NMDA RECEPTOR BLOCKADE; GENDER-DIFFERENCES; ANTIDEPRESSANT ACTIONS; DOUBLE-BLIND; KETAMINE; NEUROTRANSMISSION; COMORBIDITY; ESKETAMINE;
D O I
10.1038/s41386-020-0714-z
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:1545 / 1556
页数:12
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