Ketamine as a Prophylactic Against Stress-Induced Depressive-like Behavior.
Ketamine as a Prophylactic Against Stress-Induced Depressive-like Behavior.
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DOI：
10.1016/j.biopsych.2015.04.022
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发表时间：
2016-05-01
影响因子：
10.6
通讯作者：
Denny CA
中科院分区：
文献类型：
--
作者：
Brachman RA;McGowan JC;Perusini JN;Lim SC;Pham TH;Faye C;Gardier AM;Mendez-David I;David DJ;Hen R;Denny CA
压力暴露是精神疾病的最大风险因素之一，如重度抑郁症（MDD）和创伤后应激障碍（PTSD）。然而，并不是所有暴露在压力下的人都会患上情感障碍。压力复原力，即在不发展持续性精神病理的情况下承受压力的能力，因人而异。增强高危人群的压力恢复能力可能潜在地防止压力引起的精神疾病。尽管如此，还没有发现任何增强复原力的药物。利用小鼠慢性社会失败（SD）压力模型、习得性无助（LH）和慢性皮质酮（CORT）模型，我们测试了氯胺酮(K)是否可以预防抑郁样行为。小鼠被给予单剂量的生理盐水（Sal）或氯胺酮，然后一周后进行2周的SD， LH训练或3周的CORT。SD稳健可靠地诱导对照组（Ctrl）小鼠抑郁样行为。在强迫游泳试验（FST）和显性相互作用试验（DI）中，预防性氯胺酮治疗小鼠对SD的有害作用具有保护作用。我们在LH和CORT模型中证实了这些影响。在LH模型中，训练后的逃逸潜伏期增加，而氯胺酮可以防止这种影响。在CORT模型中，单剂量氯胺酮阻断了FST、新颖性抑制进食（NSF）范式和蔗糖飞溅试验（ST）中的应激诱导行为。这些数据表明，氯胺酮可以诱导持续的应激恢复能力，因此，可能有助于防止应激引起的疾病。
Stress exposure is one of the greatest risk factors for psychiatric illnesses like Major Depressive Disorder (MDD) and Post-Traumatic Stress Disorder (PTSD). However, not all individuals exposed to stress develop affective disorders. Stress resilience, the ability to experience stress without developing persistent psychopathology, varies from individual to individual. Enhancing stress resilience in at-risk populations could potentially protect against stress-induced psychiatric disorders. Despite this fact, no resilience-enhancing pharmaceuticals have been identified. Using a chronic social defeat (SD) stress model, learned helplessness (LH), and a chronic corticosterone (CORT) model in mice, we tested if ketamine (K) could protect against depressive-like behavior. Mice were administered a single dose of saline (Sal) or ketamine and then one week later were subjected to 2 weeks of SD, LH training, or 3 weeks of CORT. SD robustly and reliably induced depressive-like behavior in control (Ctrl) mice. Mice treated with prophylactic ketamine were protected against the deleterious effects of SD in the forced swim test (FST) and in the dominant interaction (DI) test. We confirmed these effects in LH and the CORT model. In the LH model, latency to escape was increased following training—and this effect was prevented by ketamine. In the CORT model, a single dose of ketamine blocked stress-induced behavior in the FST, novelty suppressed feeding (NSF) paradigm, and the sucrose splash test (ST). These data show that ketamine can induce persistent stress resilience and, therefore, may be useful in protecting against stress-induced disorders.