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Opioid receptor system contributes to the acute and sustained antidepressant-like effects, but not the hyperactivity motor effects of ketamine in mice
Pharmacology Biochemistry and Behavior ( IF 3.6 ) Pub Date : 2021-07-02 , DOI: 10.1016/j.pbb.2021.173228
Fan Zhang 1 , Todd M Hillhouse 2 , Paige M Anderson 2 , Peyton O Koppenhaver 2 , Taylor N Kegen 2 , Sofia G Manicka 1 , Jackson T Lane 1 , Elizabeth Pottanat 1 , Madeline Van Fossen 1 , Remington Rice 1 , Joseph H Porter 1
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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.



中文翻译:

阿片受体系统有助于急性和持续的抗抑郁样作用,但不是氯胺酮对小鼠的过度运动作用

2000 年,据报道,亚麻醉剂量 (0.5 mg/kg iv) 的解离麻醉剂氯胺酮对诊断为重度抑郁症的患者具有快速而强大的抗抑郁作用,后来,氯胺酮也被证明对难治性抑郁症患者有效。耐心。然而,导致氯胺酮抗抑郁作用的机制仍不清楚。2018 年,一项临床研究报告称,非选择性阿片类拮抗剂纳曲酮的预处理减弱了氯胺酮对抑郁症患者的快速抗抑郁作用。目前的研究调查了阿片受体系统在氯胺酮的急性和持续抗抑郁样和过度活跃作用中的潜在作用。小鼠在尾悬试验 (TST) 和低速率响应差异强化 (DRL) 72 s 任务中进行了测试,这些任务是抗抑郁药样特性的行为筛选。此外,还测量了野外运动活动。在所有行为分析中,小鼠在施用氯胺酮之前用非选择性阿片受体拮抗剂纳曲酮或盐水预处理。目前的研究发现,氯胺酮(10 毫克/公斤)在 TST 中产生急性(30 分钟)和持续(24 小时)抗抑郁样作用,这种作用通过 2 毫克/公斤纳曲酮的预处理减弱。氯胺酮 (32 mg/kg) 在 DRL 72 s 任务中也产生急性抗抑郁样作用,该作用通过 2 mg/kg 纳曲酮的预处理减弱。最后,氯胺酮(10 和 32 毫克/千克)在露天场地中产生过度活跃;然而,用 2 mg/kg 纳曲酮预处理未能阻断氯胺酮的多动效应。这些结果以及最近的临床发现表明,氯胺酮的抗抑郁作用,而不是其过度活跃的作用,涉及阿片类药物系统的激活。

更新日期:2021-07-07
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