LaGamma Christina T, Tang William W, Morgan Ashlea A, McGowan Josephine Cecelia, Brachman Rebecca A, Denny Christine A
Division of Integrative Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH)/New York State Psychiatric Institute (NYSPI), New York, NY, United States.
Department of Psychiatry, Columbia University, New York, NY, United States.
Front Mol Neurosci. 2018 Nov 6;11:404. doi: 10.3389/fnmol.2018.00404. eCollection 2018.
Ketamine has been found to have rapid, long-lasting antidepressant effects in treatment-resistant (TR) patients with major depressive disorder (MDD). Recently, we have also shown that ketamine acts as a prophylactic to protect against the development of stress-induced depressive-like behavior in mice, indicating that a preventative treatment against mental illness using ketamine is possible. While there is significant investigation into ketamine's antidepressant mechanism of action, little is known about ketamine's underlying prophylactic mechanism. More specifically, whether ketamine's prophylactic action is molecularly similar to or divergent from its antidepressant action is entirely unknown. Here, we sought to characterize immunohistochemical signatures of cell populations governing ketamine's antidepressant and prophylactic effects. 129S6/SvEv mice were treated with saline (Sal) or ketamine (K) either before a social defeat (SD) stressor as a prophylactic, or after SD as an antidepressant, then subsequently assessed for depressive-like behavior. Post-fixed brains were processed for doublecortin (DCX), calretinin (CR) and calbindin (CB) expression. The number of DCX neurons in the dentate gyrus (DG) of the hippocampus (HPC) was not affected by prophylactic or antidepressant ketamine treatment, while the number of CR neurons in the ventral hilus increased with antidepressant ketamine under SD conditions. Moreover, antidepressant, but not prophylactic ketamine administration significantly altered CR and CB expression in the ventral HPC (vHPC). These data show that while antidepressant ketamine treatment mediates some of its effects via adult hippocampal markers, prophylactic ketamine administration does not, at least in 129S6/SvEv mice. These data suggest that long-lasting behavioral effects of prophylactic ketamine are independent of hippocampal DCX, CR and CB expression in stress-susceptible mice.
已发现氯胺酮对难治性（TR）重度抑郁症（MDD）患者具有快速、持久的抗抑郁作用。最近，我们还表明，氯胺酮可作为一种预防措施，防止小鼠出现应激诱导的抑郁样行为，这表明使用氯胺酮预防精神疾病是可能的。虽然对氯胺酮的抗抑郁作用机制进行了大量研究，但对其潜在的预防机制知之甚少。更具体地说，氯胺酮的预防作用在分子水平上与其抗抑郁作用是相似还是不同，目前完全未知。在此，我们试图表征控制氯胺酮抗抑郁和预防作用的细胞群的免疫组化特征。将129S6/SvEv小鼠在遭受社会挫败（SD）应激源之前作为预防措施给予生理盐水（Sal）或氯胺酮（K），或在SD之后作为抗抑郁药给予，然后评估其抑郁样行为。对固定后的大脑进行双皮质素（DCX）、钙视网膜蛋白（CR）和钙结合蛋白（CB）表达的检测。海马体（HPC）齿状回（DG）中DCX神经元的数量不受预防性或抗抑郁性氯胺酮治疗的影响，而在SD条件下，腹侧海马门中CR神经元的数量随抗抑郁性氯胺酮治疗而增加。此外，抗抑郁性氯胺酮给药（而非预防性氯胺酮给药）显著改变了腹侧HPC（vHPC）中CR和CB的表达。这些数据表明，虽然抗抑郁性氯胺酮治疗通过成年海马标记物介导其部分作用，但预防性氯胺酮给药并非如此，至少在129S6/SvEv小鼠中是这样。这些数据表明，预防性氯胺酮的长期行为效应独立于应激易感小鼠海马中的DCX、CR和CB表达。
