Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA.
Department of Psychology, University of Wisconsin Green Bay, Green Bay, WI, USA.
Pharmacol Biochem Behav. 2021 Sep;208:173228. doi: 10.1016/j.pbb.2021.173228. Epub 2021 Jul 2.
In 2000, a subanesthetic dose (0.5 mg/kg i.v.) of the dissociative anesthetic ketamine was reported to have both rapid and robust antidepressant effects in patients diagnosed with major depressive disorder and later, ketamine also was shown to be effective in treatment-resistant depressed patients. However, the mechanisms responsible for ketamine's antidepressant effects remain unclear. In 2018, a clinical study reported that pretreatment with the nonselective opioid antagonist naltrexone attenuated the rapid antidepressant effect of ketamine in depressed patients. The current study investigated the potential role of the opioid receptor system in the acute and sustained antidepressant-like and hyperactive effects of ketamine. Mice were tested in the tail suspension test (TST) and differential-reinforcement-of-low-rate responding (DRL) 72 s task which are behavioral screens for antidepressant-like properties. Additionally, open field locomotor activity also was measured. In all behavioral assays, mice were pretreated with the nonselective opioid receptor antagonist naltrexone or saline prior to ketamine administration. The current study found that ketamine (10 mg/kg) produced acute (30 min) and sustained (24 h) antidepressant-like effects in TST, which were attenuated by pretreatment of 2 mg/kg naltrexone. Ketamine (32 mg/kg) also produced an acute antidepressant-like effect in the DRL 72 s task that was attenuated by pretreatment of 2 mg/kg naltrexone. Finally, ketamine (10 and 32 mg/kg) produced hyperactivity in the open field; however, pretreatment with 2 mg/kg naltrexone failed to block the hyperactivity effects ketamine. These results, along with recent clinical findings, suggest that ketamine's antidepressant effects, but not its hyperactive effects, involve activation of the opioid system.
2000 年，有研究报道称，亚麻醉剂量（0.5mg/kg，静脉注射）的分离麻醉剂氯胺酮可迅速且显著改善重度抑郁症患者的抑郁症状，随后，氯胺酮在治疗抵抗性抑郁症患者中也显示出有效作用。然而，氯胺酮抗抑郁作用的确切机制仍不清楚。2018 年，一项临床研究报道，预先给予非选择性阿片受体拮抗剂纳曲酮可减弱氯胺酮对抑郁症患者的快速抗抑郁作用。本研究旨在探讨阿片受体系统在氯胺酮的急性和慢性抗抑郁样和多动样作用中的潜在作用。在悬尾试验（TST）和差频强化反应（DRL）72s 任务中测试了小鼠，这两种方法可作为抗抑郁样特性的行为筛选。此外，还测量了开阔场运动活动。在所有行为测定中，小鼠在给予氯胺酮之前预先给予非选择性阿片受体拮抗剂纳曲酮或生理盐水。本研究发现，氯胺酮（10mg/kg）在 TST 中产生急性（30 分钟）和慢性（24 小时）抗抑郁样作用，而 2mg/kg 纳曲酮预处理可减弱这种作用。氯胺酮（32mg/kg）也在 DRL 72s 任务中产生急性抗抑郁样作用，而 2mg/kg 纳曲酮预处理可减弱这种作用。最后，氯胺酮（10 和 32mg/kg）在开阔场中产生多动样作用；然而，2mg/kg 纳曲酮预处理未能阻断氯胺酮的多动样作用。这些结果与最近的临床发现一起表明，氯胺酮的抗抑郁作用，而不是其多动样作用，涉及阿片系统的激活。
