期刊
NEUROPSYCHOPHARMACOLOGY
卷 31, 期 10, 页码 2121-2131出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.npp.1301029
关键词
serotonin; transporter; cytokines; IL-1 beta; TNF-alpha; p38 MAPK
资金
- NIDA NIH HHS [DA07390] Funding Source: Medline
Proinflammatory cytokines and serotonergic homeostasis have both been implicated in the pathophysiology of major psychiatric disorders. We have demonstrated that activation of p38 mitogen-activated protein kinase (MAPK) induces a catalytic activation of the serotonin transporter (SERT) arising from a reduction in the SERT K-m for 5-hydroxytryptamine (5-HT). As inflammatory cytokines can activate p38 MAPK, we hypothesized that they might also activate neuronal SERT. Indeed, Interleukin-1beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) stimulated serotonin uptake in both the rat embryonic raphe cell line, RN46A, and in mouse midbrain and striatal synaptosomes. In RN46A cells, IL-1 beta stimulated 5-HT uptake in a dose-and time-dependent manner, peaking in 20 min at 100 ng/ml. This was abolished by IL-1ra (20 ng/ml), an antagonist of the IL-1 receptor, and by SB203580 (5 mu M), a p38 MAPK inhibitor. TNF-alpha also dose- and time-dependently stimulated 5-HT uptake that was only partially blocked by SB203580. Western blots showed that IL-1 beta and TNF- a activated p38 MAPK, in an SB203580-sensitive manner. IL-1 beta induced an SB203580-sensitive decrease in 5-HT K-m with no significant change in Vmax. In contrast, TNF-alpha stimulation decreased 5-HT K-m and increased SERT Vmax. SB203580 selectively blocked the TNF-alpha-induced change in SERT Km. In mouse midbrain and striatal synaptosomes, maximal stimulatory effects on 5-HT uptake occurred at lower concentrations (IL-1 beta, 10 ng/ml; TNF-alpha, 20 ng/ml), and over shorter incubation times (10 min). As with RN46A cells, the effects of IL-1 beta and TNF-alpha were completely (IL-1 beta) or partially (TNF-alpha) blocked by SB203580. These results provide the first evidence that proinflammatory cytokines can acutely regulate neuronal SERT activity via p38 MAPK-linked pathways.
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