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The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders.
Molecular Psychiatry ( IF 9.6 ) Pub Date : 2018-01-01 , DOI: 10.1038/mp.2017.190
M Kokkinou , A H Ashok , O D Howes

Ketamine is a non-competitive antagonist at the N-methyl-d-aspartate receptor. It has recently been found to have antidepressant effects and is a drug of abuse, suggesting it may have dopaminergic effects. To examine the effect of ketamine on the dopamine systems, we carried out a systematic review and meta-analysis of dopamine measures in the rodent, human and primate brain following acute and chronic ketamine administration relative to a drug-free baseline or control condition. Systematic search of PubMed and PsychInfo electronic databases yielded 40 original peer-reviewed studies. There were sufficient rodent studies of the acute effects of ketamine at sub-anaesthetic doses for meta-analysis. Acute ketamine administration in rodents is associated with significantly increased dopamine levels in the cortex (Hedge's g= 1.33, P<0.01), striatum (Hedge's g=0.57, P<0.05) and the nucleus accumbens (Hedge's g=1.30, P<0.05) compared to control conditions, and 62-180% increases in dopamine neuron population activity. Sub-analysis indicated elevations were more marked in in vivo (g=1.93) than ex vivo (g=0.50) studies. There were not enough studies for meta-analysis in other brain regions studied (hippocampus, ventral pallidum and cerebellum), or of the effects of chronic ketamine administration, although consistent increases in cortical dopamine levels (from 88 to 180%) were reported in the latter studies. In contrast, no study showed an effect of anaesthetic doses (>100 mg kg-1) of ketamine on dopamine levels ex vivo, although this remains to be tested in vivo. Findings in non-human primates and in human studies using positron emission tomography were not consistent. The studies reviewed here provide evidence that acute ketamine administration leads to dopamine release in the rodent brain. We discuss the inter-species variation in the ketamine induced dopamine release as well as the implications for understanding psychiatric disorders, in particular substance abuse, schizophrenia, and the potential antidepressant properties of ketamine, and comparisons with stimulants and other NMDA antagonists. Finally we identify future research needs.

中文翻译:

氯胺酮对多巴胺能功能的影响:荟萃分析和对神经精神疾病的影响的审查。

氯胺酮是N-甲基-d-天冬氨酸受体的非竞争性拮抗剂。最近发现它具有抗抑郁作用,是一种滥用药物,表明它可能具有多巴胺能作用。为了检查氯胺酮对多巴胺系统的影响,我们相对于无药物基线或对照条件,在急性和慢性氯胺酮给药后,对啮齿动物,人和灵长类动物脑中的多巴胺措施进行了系统的综述和荟萃分析。系统搜索PubMed和PsychInfo电子数据库产生了40篇经过同行评审的原始研究。对于亚麻醉剂量的氯胺酮的急性作用,有足够的啮齿类动物研究用于荟萃分析。在啮齿动物中急性给予氯胺酮与皮质中的多巴胺水平显着升高有关(Hedge's g = 1.33,P <0.01),与对照组相比,纹状体(Hedge's g = 0.57,P <0.05)和伏隔核(Hedge's g = 1.30,P <0.05)和多巴胺神经元种群活动增加了62-180%。次分析表明,体内研究(g = 1.93)的升高明显高于离体研究(g = 0.50)。尽管在研究的其他大脑区域(海马,腹侧苍白球和小脑)或长期服用氯胺酮的影响方面,尚无足够的荟萃分析研究,或长期服用氯胺酮的影响。后来的研究。相反,没有研究显示麻醉剂量(> 100 mg kg 次分析表明,体内研究(g = 1.93)的升高明显高于离体研究(g = 0.50)。尽管在研究中报告了皮质多巴胺水平持续增加(从88%增至180%),但在其他研究的大脑区域(海马,腹侧苍白球和小脑)或长期服用氯胺酮的影响方面,没有足够的荟萃分析研究。后来的研究。相反,没有研究显示麻醉剂量(> 100 mg kg 次分析表明,体内研究(g = 1.93)的升高明显高于离体研究(g = 0.50)。尽管在研究中报告了皮质多巴胺水平持续增加(从88%增至180%),但在其他研究的大脑区域(海马,腹侧苍白球和小脑)或长期服用氯胺酮的影响方面,没有足够的荟萃分析研究。后来的研究。相反,没有研究显示麻醉剂量(> 100 mg kg(-1)氯胺酮对多巴胺水平的影响离体,尽管尚待体内测试。在非人类灵长类动物和使用正电子发射断层扫描技术的人类研究中,发现并不一致。此处审查的研究提供了证据,表明急性给予氯胺酮会导致啮齿动物大脑中的多巴胺释放。我们讨论了氯胺酮引起的多巴胺释放的物种间差异,以及对于理解精神疾病(特别是滥用药物,精神分裂症和氯胺酮潜在的抗抑郁特性)的意义,以及与兴奋剂和其他NMDA拮抗剂的比较。最后,我们确定未来的研究需求。
更新日期:2018-01-03
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