Prophylactic Ketamine Attenuates Learned Fear
Prophylactic Ketamine Attenuates Learned Fear
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DOI：
10.1038/npp.2017.19
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发表时间：
2017-07-01
影响因子：
7.6
通讯作者：
Denny, Christine A.
中科院分区：
文献类型：
--
作者：
McGowan, Josephine C.;LaGamma, Christina T.;Denny, Christine A.
据报道，氯胺酮是一种有效的抗抑郁药，用于治疗重度抑郁症和创伤后应激障碍。最近，氯胺酮也被证明可以预防小鼠应激诱导的抑郁样行为。然而，为了最大限度地发挥其抗抑郁和/或预防作用，氯胺酮何时应相对于应激源给药仍然未知。此外，尚不清楚氯胺酮是否可以预防随后的应激源。我们在相对于恐惧体验的不同时间点系统地给予氯胺酮，以确定何时氯胺酮在减少恐惧表达或防止恐惧再激活方面最有效。使用情境恐惧条件反射（CFC）范例，在CFC之前或之后的不同时间点向小鼠施用单剂量的盐水或氯胺酮（30 mg/kg）。与给予生理盐水的小鼠相比，给予预防性氯胺酮1周（而不是CFC前1个月或1小时）的小鼠表现出减少的冻结行为。相反，氯胺酮给药后CFC或在灭绝并没有改变随后的恐惧表达。然而，在恢复之前给予氯胺酮增加了在开阔场地的直立回合次数，可能表明注意力增加。这些数据表明，氯胺酮可以缓冲恐惧反应时，给予一周前作为预防，但不是当之前或之后立即给予应激诱导事件。因此，氯胺酮可能是最有用的临床，如果在预防性的方式给药前1周的紧张性刺激，以防止恐惧反应加剧厌恶刺激。
Ketamine has been reported to be an efficacious antidepressant for major depressive disorder and posttraumatic stress disorder. Most recently, ketamine has also been shown to be prophylactic against stress-induced depressive-like behavior in mice. It remains unknown, however, when ketamine should be administered relative to a stressor in order to maximize its antidepressant and/or prophylactic effects. Moreover, it is unknown whether ketamine can be prophylactic against subsequent stressors. We systematically administered ketamine at different time points relative to a fear experience, in order to determine when ketamine is most effective at reducing fear expression or preventing fear reactivation. Using a contextual fear conditioning (CFC) paradigm, mice were administered a single dose of saline or ketamine (30 mg/kg) at varying time points before or after CFC. Mice administered prophylactic ketamine 1 week, but not 1 month or 1 h before CFC, exhibited reduced freezing behavior when compared with mice administered saline. In contrast, ketamine administration following CFC or during extinction did not alter subsequent fear expression. However, ketamine administered before reinstatement increased the number of rearing bouts in an open field, possibly suggesting an increase in attentiveness. These data indicate that ketamine can buffer a fear response when given a week before as prophylactic, but not when given immediately before or after a stress-inducing episode. Thus, ketamine may be most useful in the clinic if administered in a prophylactic manner 1 week before a stressor, in order to protect against heightened fear responses to aversive stimuli.