Chen Briana K, Luna Victor M, LaGamma Christina T, Xu Xiaoming, Deng Shi-Xian, Suckow Raymond F, Cooper Thomas B, Shah Abhishek, Brachman Rebecca A, Mendez-David Indira, David Denis J, Gardier Alain M, Landry Donald W, Denny Christine A
Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY, 10027, USA.
Division of Systems Neuroscience, Research Foundation for Mental Hygiene Inc. (RFMH)/New York State Psychiatric Institute (NYSPI), New York, NY, 10032, USA.
Neuropsychopharmacology. 2020 Aug;45(9):1545-1556. doi: 10.1038/s41386-020-0714-z. Epub 2020 May 17.
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.
增强高危人群的应激恢复力可显著降低与应激相关的精神疾病的发病率。我们之前报道过，给予（R,S）-氯胺酮可预防雄性小鼠应激诱导的抑郁样行为，可能是通过改变海马CA3区中α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）介导的神经传递。然而，（R,S）-氯胺酮的代谢产物在两性中是否具有预防作用仍不清楚。在129S6/SvEv雄性和雌性小鼠遭受多种应激源之一前1周，我们给予不同剂量的（R,S）-氯胺酮或其代谢产物（2R,6R）-羟基去甲氯胺酮（（2R,6R）-HNK）和（2S,6S）-羟基去甲氯胺酮（（2S,6S）-HNK）。采用膜片钳电生理学方法来确定预防性给药对CA3区谷氨酸能活性的影响。为了研究卵巢激素与应激恢复力之间的相互作用，雌性小鼠在给药前还接受了卵巢切除术（OVX）手术和激素替代方案。（2S,6S）-HNK和（2R,6R）-HNK对两性中不同的应激诱导行为均有保护作用，其中（2S,6S）-HNK减轻雄性小鼠的习得性恐惧，而（2R,6R）-HNK预防两性中应激诱导的抑郁样行为。（R,S）-氯胺酮和（2R,6R）-HNK，但不是（2S,6S）-HNK，减弱了海马CA3区中由AMPAR介导的大幅度爆发。给药1周后，所有三种化合物均降低了N-甲基-D-天冬氨酸受体（NMDAR）介导的电流。此外，卵巢衍生的激素对于恢复雌性小鼠中（R,S）-氯胺酮和（2R,6R）-HNK介导的预防作用是必要且充分的。我们的数据进一步证明，增强恢复力的预防性药物可能会改变CA3区中AMPAR介导的谷氨酸能传递。此外，我们表明针对应激诱导的抑郁样行为的预防性药物可以以性别特异性的方式开发，并证明卵巢激素对于（R,S）-氯胺酮和（2R,6R）-HNK在雌性小鼠中的预防效果是必要的。
