Korte-Bouws Gerdien A H, van Heesch Floor, Westphal Koen G C, Ankersmit Lisa M J, van Oosten Edwin M, Güntürkün Onur, Korte S Mechiel
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Faculty of Science, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
Department of Biopsychology, Faculty of Psychology, Ruhr-Universität Bochum, Universitätsstraße 150, D-44780 Bochum, Germany.
Pharmaceuticals (Basel). 2018 Jul 5;11(3):66. doi: 10.3390/ph11030066.
It is well known that bacterial lipopolysaccharides (LPS) both increases proinflammatory cytokines and produces sickness behavior, including fatigue and anhedonia (i.e., the inability to experience pleasure). Previously, we have shown that intraperitoneally (i.p.) administered LPS increased extracellular monoamine metabolite levels in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), which was completely, or at least partly, prevented by pretreatment with a triple reuptake inhibitor that also blocks the serotonin (5-HT) transporter (SERT). This suggests indirectly, that LPS may enhance SERT transporter activity, and consequently, increase removal of 5-HT from the synaptic cleft, and increase metabolism of 5-HT. In the present study, we focus more specifically on the role of SERT in this increased metabolism by using rats, that differ in SERT expression. Therefore, the effects of an intraperitoneal LPS injection on extracellular concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were investigated by in vivo microdialysis in the NAc and mPFC of wild type (SERT), heterozygous (SERT) and knockout (SERT) rats. Here, we show that LPS-induced 5-HIAA formation in male rats, is significantly increased in SERT rats in both the NAc and mPFC, whereas this increase is partly or totally abolished in SERT and SERT rats, respectively. Thus, the present study supports the hypothesis that systemic LPS in male rats increases SERT function and consequently enhances 5-HT uptake and metabolism in both the NAc and mPFC.
众所周知，细菌脂多糖（LPS）既能增加促炎细胞因子，又会引发疾病行为，包括疲劳和快感缺失（即无法体验愉悦感）。此前，我们已经表明，腹腔注射LPS会增加伏隔核（NAc）和内侧前额叶皮质（mPFC）中的细胞外单胺代谢物水平，而预先用一种也能阻断血清素（5-HT）转运体（SERT）的三重再摄取抑制剂进行预处理，可完全或至少部分地预防这种情况。这间接表明，LPS可能会增强SERT转运体的活性，从而增加5-HT从突触间隙的清除，并增加5-HT的代谢。在本研究中，我们通过使用SERT表达不同的大鼠，更具体地关注SERT在这种代谢增加中的作用。因此，通过体内微透析在野生型（SERT）、杂合型（SERT）和敲除型（SERT）大鼠的NAc和mPFC中研究了腹腔注射LPS对5-HT及其代谢物5-羟吲哚乙酸（5-HIAA）细胞外浓度的影响。在这里，我们表明，LPS诱导的雄性大鼠5-HIAA形成，在NAc和mPFC中的SERT大鼠中均显著增加，而在SERT和SERT大鼠中，这种增加分别部分或完全被消除。因此，本研究支持以下假设：雄性大鼠体内的全身性LPS会增加SERT功能，从而增强NAc和mPFC中5-HT的摄取和代谢。
