Asokan Aditya, Ball Alan R, Laird Christina D, Hermer Linda, Ormerod Brandi K
J. Crayton Pruitt Family Department of Biomedical Engineering and Evelyn F. & William L. McKnight Brain Institute, University of Florida, Gainesville, Florida, United States of America.
J. Crayton Pruitt Family Department of Biomedical Engineering and Evelyn F. & William L. McKnight Brain Institute, University of Florida, Gainesville, Florida, United States of America; Department of Psychology and Behavioral Neuroscience Program, University of Florida, Gainesville, Florida, United States of America.
PLoS One. 2014 Jun 4;9(6):e98530. doi: 10.1371/journal.pone.0098530. eCollection 2014.
Adult hippocampal neurogenesis has been linked to the effects of anti-depressant drugs on behavior in rodent models of depression. To explore this link further, we tested whether the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine impacted adult hippocampal neurogenesis differently than its primary active SNRI metabolite desvenlafaxine. Adult male Long Evans rats (n = 5-6 per group) were fed vehicle, venlafaxine (0.5 or 5 mg) or desvenlafaxine (0.5 or 5 mg) twice daily for 16 days. Beginning the third day of drug treatment, the rats were given a daily bromodeoxyuridine (BrdU; 50 mg/kg) injection for 5 days to label dividing cells and then perfused 2 weeks after the first BrdU injection to confirm total new hippocampal cell numbers and their phenotypes. The high desvenlafaxine dose increased total new BrdU+ cell number and appeared to accelerate neuronal maturation because fewer BrdU+ cells expressed maturing neuronal phenotypes and more expressed mature neuronal phenotypes in the dentate gyri of these versus vehicle-treated rats. While net neurogenesis was not increased in the dentate gyri of rats treated with the high desvenlafaxine dose, significantly more mature neurons were detected. Our data expand the body of literature showing that antidepressants impact adult neurogenesis by stimulating NPC proliferation and perhaps the survival of neuronal progeny and by showing that a high dose of the SNRI antidepressant desvenlafaxine, but neither a high nor low venlafaxine dose, may also accelerate neuronal maturation in the adult rat hippocampus. These data support the hypothesis that hippocampal neurogenesis may indeed serve as a biomarker of depression and the effects of antidepressant treatment, and may be informative for developing novel fast-acting antidepressant strategies.
在抑郁症啮齿动物模型中，成年海马神经发生与抗抑郁药物对行为的影响有关。为了进一步探究这种联系，我们测试了5-羟色胺-去甲肾上腺素再摄取抑制剂（SNRI）文拉法辛与其主要活性SNRI代谢物去甲文拉法辛对成年海马神经发生的影响是否不同。成年雄性Long Evans大鼠（每组n = 5-6只）每天两次喂食赋形剂、文拉法辛（0.5或5毫克）或去甲文拉法辛（0.5或5毫克），持续16天。从药物治疗的第三天开始，每天给大鼠注射一次溴脱氧尿苷（BrdU；50毫克/千克），持续5天，以标记分裂细胞，然后在第一次BrdU注射后2周进行灌注，以确认海马中新生成细胞的总数及其表型。高剂量去甲文拉法辛增加了新生成的BrdU+细胞总数，并且似乎加速了神经元成熟，因为与接受赋形剂治疗的大鼠相比，这些大鼠齿状回中表达成熟神经元表型的BrdU+细胞更少，而表达成熟神经元表型的更多。虽然高剂量去甲文拉法辛治疗的大鼠齿状回中的净神经发生没有增加，但检测到的成熟神经元明显更多。我们的数据扩展了文献，表明抗抑郁药通过刺激神经前体细胞增殖以及可能通过神经元后代的存活来影响成年神经发生，并且表明高剂量的SNRI抗抑郁药去甲文拉法辛，但不是高剂量或低剂量的文拉法辛，也可能加速成年大鼠海马中的神经元成熟。这些数据支持了海马神经发生可能确实是抑郁症和抗抑郁治疗效果的生物标志物这一假设，并且可能为开发新型速效抗抑郁策略提供信息。
