Benmansour Saloua, Deltheil Thierry, Piotrowski Jonathan, Nicolas Lorelei, Reperant Christelle, Gardier Alain M, Frazer Alan, David Denis J
Department of Pharmacology, University of Texas Health Science Center at San Antonio, Texas 78229, USA.
Eur J Pharmacol. 2008 Jun 10;587(1-3):90-8. doi: 10.1016/j.ejphar.2008.03.048. Epub 2008 Apr 4.
Whereas SSRIs produce rapid blockade of the serotonin transporter (SERT) in vitro and in vivo, the onset of an observable clinical effect takes longer to occur and a variety of pharmacological effects caused by antidepressants have been speculated to be involved either in initiating antidepressant effects and/or enhancing their effects on serotonergic transmission so as to cause clinical improvement. Among such secondary factors is increased activity of brain-derived neurotrophic factor (BDNF), which requires the Tropomyosine-related kinase B receptor (TrkB) for its effects. To begin an analysis of the influence of BDNF on serotonergic activity, we studied the acute effects of BDNF on SERT activity. A single BDNF injection (either intracerebroventricularly or directly into the CA3 region of hippocampus) decreased the signal amplitude and clearance rate produced by exogenously applied 5-HT compared to what was measured in control rats, shown using in vivo chronoamperometry. It also reduced the ability of a locally applied SSRI to block the clearance of 5-HT. In awake freely moving mice, acute intrahippocampal injection of BDNF decreased extracellular levels of 5-HT in the hippocampus, as measured using microdialysis. In addition, perfusion with BDNF decreased KCl-evoked elevations of 5-HT. These effects of BDNF were blocked by the non-selective antagonist of TrkB receptors, K252a. Overall, it may be inferred that in the hippocampus, through TrkB activation, a single injection of BDNF enhances SERT function. Such acute effects of BDNF would be expected to counter early effects of SSRIs, which might, in part, account for some delay in therapeutic effect.
尽管选择性5-羟色胺再摄取抑制剂（SSRI）在体外和体内能迅速阻断5-羟色胺转运体（SERT），但可观察到的临床疗效的出现需要更长时间，并且推测抗抑郁药引起的多种药理作用要么参与启动抗抑郁作用，和/或增强其对5-羟色胺能传递的作用，从而导致临床改善。这类次要因素包括脑源性神经营养因子（BDNF）活性增加，其发挥作用需要原肌球蛋白相关激酶B受体（TrkB）。为了开始分析BDNF对5-羟色胺能活性的影响，我们研究了BDNF对SERT活性的急性作用。与对照大鼠相比，单次脑室内注射或直接注射到海马CA3区的BDNF降低了外源性应用5-羟色胺（5-HT）产生的信号幅度和清除率，这是通过体内计时电流法测得的。它还降低了局部应用的SSRI阻断5-HT清除的能力。在清醒自由活动的小鼠中，海马内急性注射BDNF降低了海马中5-HT的细胞外水平，这是通过微透析法测得的。此外，用BDNF灌注可降低氯化钾诱发的5-HT升高。BDNF的这些作用被TrkB受体的非选择性拮抗剂K252a阻断。总体而言，可以推断在海马中，通过TrkB激活，单次注射BDNF可增强SERT功能。BDNF的这种急性作用预计会抵消SSRI的早期作用，这可能部分解释了治疗效果的一些延迟。
