Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8240 Risskov, Denmark; Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, Campus USP-Ribeirão Preto, Ribeirão Preto, SP 14040-904, Brazil.
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8240 Risskov, Denmark.
Eur J Pharmacol. 2017 Nov 15;815:304-311. doi: 10.1016/j.ejphar.2017.09.029. Epub 2017 Sep 22.
The rapid and sustained antidepressant properties of ketamine provide evidence of the importance of the glutamatergic system in the neurobiology of depression. The antidepressant-like effects of ketamine are dependent on brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) in limbic brain areas. The nitrergic system is closely related to the glutamatergic system and generates antidepressant-like effects when blocked. The aim of this study was to investigate whether the behavioural effects induced by the inhibition of nitric oxide (NO) synthesis by aminoguanidine or N-methyl-D-aspartate (NMDA) receptor blockade by ketamine would affect the gene expression of Bdnf and Mtor in the ventromedial prefrontal cortex in rats. The effects of ketamine or aminoguanidine were investigated in Sprague-Dawley (SD) rats, the Flinders Sensitive Line (FSL), a genetic rat model of depression, and their controls, the Flinders Resistant Line (FRL) rats. In the studies, the three protocols evaluated to which the animals/rats were exposed were: (1) pre-test and test sessions of forced swim test (FST), (2) pre-test session of FST alone, or (3) not exposed to the FST. Ketamine and aminoguanidine both induce antidepressant-like effects in SD and FSL rats. Quantitative real-time polymerase chain reaction analyses in SD rats demonstrated that none of the treatments can change the Bdnf or Mtor gene expression, but in FSL rats the treatment with ketamine increased only Bdnf gene expression. The data obtained strengthens the role of NMDA antagonists and NO inhibitors as potential antidepressant drugs, albeit with different effects on Bdnf gene expression.
氯胺酮具有快速和持续的抗抑郁作用，这为谷氨酸能系统在抑郁症的神经生物学中的重要性提供了证据。氯胺酮的抗抑郁作用依赖于脑源性神经营养因子（BDNF）和哺乳动物雷帕霉素靶蛋白（mTOR）在边缘脑区。氮能系统与谷氨酸能系统密切相关，当被阻断时会产生抗抑郁作用。本研究旨在探讨抑制一氧化氮（NO）合成的氨基胍或 NMDA 受体阻断剂氯胺酮引起的行为效应是否会影响大鼠腹侧前额叶皮层中 Bdnf 和 Mtor 的基因表达。在 Sprague-Dawley（SD）大鼠、抑郁的遗传大鼠模型 Flinders 敏感系（FSL）及其对照 Flinders 抗性系（FRL）大鼠中研究了氯胺酮或氨基胍的作用。在研究中，评估了动物/大鼠接触的三种方案：（1）强迫游泳试验（FST）的预测试和测试阶段，（2）仅 FST 的预测试阶段，或（3）未暴露于 FST。氯胺酮和氨基胍均可在 SD 和 FSL 大鼠中诱导抗抑郁作用。SD 大鼠的实时定量聚合酶链反应分析表明，这些处理均不能改变 Bdnf 或 Mtor 基因表达，但氯胺酮处理仅增加了 Bdnf 基因表达。这些数据强化了 NMDA 拮抗剂和 NO 抑制剂作为潜在抗抑郁药物的作用，尽管它们对 Bdnf 基因表达的影响不同。
